Conditions: Healthy
Keywords: Tepotinib Bioequivalence Pharmacokinetics
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 18
Healthy volunteers: yes

Brief summary:
This study investigated the bioequivalence of the 100 milligrams (mg) and 250 mg dose strengths of tepotinib tablet formulation 3 (TF3) when administered at the same dose under fasted condition.

Detailed description:

Arms:
arm 1: Participants received a single oral dose of test treatment of tepotinib TF3 (5 \* 100 mg) in treatment period 1 followed by a single oral dose of reference treatment of tepotinib TF3 (2 \* 250 mg) in treatment period 2. The treatment periods were separated by 21 day washout period. arm 2: Participants received a single oral dose of reference treatment of tepotinib TF3 (2 \* 250 mg) in treatment period 1 followed by a single oral dose of test treatment of tepotinib TF3 (5 \* 100 mg) in treatment period 2. The treatment periods were separated by 21 day washout period.

Interventions: intervention 1: Tepotinib 100 mg intervention 2: Tepotinib 250 mg
Intervention descriptions: intervention 1: Participants received a single oral dose of test treatment of tepotinib TF3 (5 \* 100 mg) in either treatment period 1 or 2. intervention 2: Participants received a single oral dose of reference treatment of tepotinib TF3 (2 \* 250 mg) in either treatment period 1 or 2.

Protocol document:
Prot_000.pdf: 
Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg 
TF3 of tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
1/1
Appendix 16.1.1
List of Protocols and Protocol Amendments
Protocol Version 1.0, 05 September 2019
Page 1 of 66


Te p oti ni b ( M S C 2 1 5 6 1 1 9 J)
Bi oe q ui v ale nce of 5 t a blets of 1 0 0 m g vs 2 t a blets of  25 0 m g T F 3 of 
te p oti ni b
M S 2 0 0 0 9 5 _ 0 0 3 8
C O N F I D E N T I A L
I N F O R M A T I O N
1/ 6 5
Cli nic al Tri al Pr ot oc ol
Cli nic al Tri al Pr ot oc ol N u m ber
M S 2 0 0 0 9 5 _ 0 0 3 8
Title
A n o pe n -la bel, si n gle-d ose, ra n d o mize d, 2-peri o d, 
2- se q ue nce cr oss -o ver, si n gle-ce nter P hase I trial i n 
healt h y  su bjects t o assess t he bi oe q ui vale nce of 
te p oti ni b ta blet f or m ulati o n 3 a d mi nistere d as 
5 ta blets of 1 0 0 m g vers us 2 ta blets of 2 5 0 m g d ose 
stre n gt h.
P h ase
1
I N D N u m ber
N ot a p plica ble
E u dr a C T N u m ber
2 0 1 9- 0 0 3 5 7 8- 1 3
Pri nci p al I n vesti g at or
 
 Ger ma n y
S p o ns or
Merc k Healt hcare K Ga A
a n affiliate of Merc k K Ga A, Dar msta dt, Ger ma n y
Fra n kf urter Str. 2 5 0
Dar msta dt, Ger ma n y
Me dical Res p o nsi ble:
 
Merc k Healt hcare K Ga A, Fra n kf urter Strasse 2 5 0, 
6 4 2 9 3 Dar msta dt, Ger ma n y
P h o ne: 
M o bile: 
Cli nic al 
Tri al Pr ot oc ol D ate 
/ 
Versi o n
0 5- Se p - 2 0 1 9 / Versi o n 1. 0
Re pl aces Versi o n
N ot a p plica ble
- C o nfi de ntial -
T his d oc u me nt is t he pr o pert y  of Merc k K Ga A, Dar msta dt, Ger ma ny, or o ne of its s u bsi diaries. 
It is i nte n de d f or restricte d use o nl y a n d ma y n ot – i n f ull or part – be passe d o n, re pr o d uce d, 
p u blis he d or use d wit h o ut e x press per missi o n of Merc k K Ga A, Dar msta dt, Ger ma n y, or its 
s u bsi diar y. C o p yri g ht © 2 0 1 9 b y  Merc k K Ga A, Dar msta dt, Ger ma ny, or its s u bsi diar y . All ri g hts 
reser ve d.
D oc u me nt N o. 0 9 0 0 ba be 8 1 2c d 5a 9 v 1. 0
O bject N o. 0 9 0 0 ba be 8 1 2 d 9 4 8a
Pa ge 2 of 6 6
PI
PI
PI
PI
PI


Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
2/65
Protocol Table of Contents
Protocol Table of Contents ..................................................................................................2
Table of In-Text Tables .......................................................................................................6
Table of In-Text Figures......................................................................................................6
List of Abbreviations ...........................................................................................................7
1
Synopsis................................................................................................9
2
Sponsor, Investigators and Trial Administrative Structure ................15
3
Background Information.....................................................................15
3.1
Trial Rationale ....................................................................................17
3.2
Risk/Benefit Assessment ....................................................................17
4
Trial Objectives ..................................................................................18
4.1
Primary Objectives .............................................................................18
4.2
Secondary Objectives .........................................................................18
4.3
Exploratory Objectives .......................................................................19
5
Investigational Plan ............................................................................19
5.1
Overall Trial Design and Plan ............................................................19
5.2
Discussion of Trial Design .................................................................20
5.2.1
Inclusion of Special Populations ........................................................21
5.2.2
Scientific Rationale for Trial Design..................................................21
5.2.3
Justification for Dose..........................................................................21
5.2.4
Rationale for Endpoints......................................................................22
5.3
Selection of Trial Population..............................................................22
5.3.1
Inclusion Criteria ................................................................................22
5.3.2
Exclusion Criteria...............................................................................23
5.4
Criteria for Initiation of Trial Treatment ............................................24
5.5
Criteria for Subject Withdrawal..........................................................24
5.5.1
Withdrawal from Trial Therapy..........................................................24
5.5.2
Withdrawal from the Trial..................................................................25
5.6
Premature Termination of the Trial ....................................................26
5.7
Definition of End of Trial...................................................................26
6
Investigational Medicinal Product and Other Drugs Used in the 
Trial.....................................................................................................27
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Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
3/65
6.1
Description of the Investigational Medicinal Products ......................27
6.2
Dosage and Administration ................................................................27
6.3
Assignment to Treatment Groups.......................................................28
6.4
Non-investigational Medicinal Products to be Used ..........................28
6.5
Concomitant Medications and Therapies ...........................................28
6.5.1
Permitted Medicines...........................................................................29
6.5.2
Prohibited Medicines..........................................................................29
6.5.3
Permitted / Prohibited Procedures ......................................................29
6.5.4
Other Interventions.............................................................................30
6.5.5
Special Precautions.............................................................................30
6.5.6
Management of Specific Adverse Events or Adverse Drug 
Reactions.............................................................................................30
6.6
Packaging and Labeling of the Investigational Medicinal Product....30
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product...............................................................................30
6.8
Investigational Medicinal Product Accountability.............................31
6.9
Assessment of Investigational Medicinal Product Compliance .........32
6.10
Blinding ..............................................................................................32
6.11
Emergency Unblinding.......................................................................32
6.12
Treatment of Overdose .......................................................................32
6.13
Medical Care of Subjects after End of Trial.......................................32
7
Trial Procedures and Assessments......................................................32
7.1
Schedule of Assessments....................................................................32
7.1.1
Screening Examination.......................................................................33
7.1.2
Treatment Periods...............................................................................34
7.1.3
End of Trial Visit................................................................................35
7.2
Demographic and Other Baseline Characteristics ..............................36
7.3
Efficacy Assessments .........................................................................36
7.4
Assessment of Safety..........................................................................36
7.4.1
Adverse Events...................................................................................37
7.4.2
Pregnancy and In Utero Drug Exposure.............................................41
7.4.3
Clinical Laboratory Assessments .......................................................42
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Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
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MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
4/65
7.4.4
Vital Signs, Physical Examinations, and Other Assessments.............45
7.5
Pharmacokinetics................................................................................46
7.5.1
Blood Sampling ..................................................................................46
7.5.2
Calculation of Pharmacokinetic Variables .........................................47
7.6
Biomarkers..........................................................................................47
7.7
Pharmacogenetics ...............................................................................48
7.8
Other Assessments..............................................................................48
8
Statistics..............................................................................................48
8.1
Statistical Hypotheses.........................................................................48
8.2
Sample Size ........................................................................................49
8.3
Randomization....................................................................................49
8.4
Endpoints............................................................................................50
8.4.1
Primary Endpoints ..............................................................................50
8.4.2
Secondary Endpoints ..........................................................................50
8.4.3
Exploratory Endpoints........................................................................50
8.5
Analysis Sets.......................................................................................50
8.5.1
Safety Analysis Set.............................................................................50
8.5.2
Definition of Pharmacokinetic Analysis Set.......................................50
8.6
Description of Statistical Analyses.....................................................51
8.6.1
General Considerations.......................................................................51
8.6.2
Analysis of Primary Endpoints...........................................................52
8.6.3
Analysis of Secondary Endpoints.......................................................52
8.6.4
Analysis of Safety and Exploratory Endpoints...................................52
8.7
Interim and Additional Planned Analyses ..........................................53
9
Ethical and Regulatory Aspects..........................................................53
9.1
Responsibilities of the Investigator ....................................................53
9.2
Subject Information and Informed Consent .......................................53
9.3
Subject Identification and Privacy......................................................54
9.4
Emergency Medical Support and Subject Card..................................54
9.5
Clinical Trial Insurance and Compensation to Subjects.....................54
9.6
Independent Ethics Committee or Institutional Review Board ..........55
9.7
Health Authorities...............................................................................55
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Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
5/65
10
Trial Management...............................................................................55
10.1
Case Report Form Handling...............................................................55
10.2
Source Data and Subject Files............................................................56
10.3
Investigator Site File and Archiving...................................................56
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities ..........................................................................................57
10.5
Changes to the Clinical Trial Protocol................................................57
10.6
Clinical Trial Report and Publication Policy......................................57
10.6.1
Clinical Trial Report...........................................................................57
10.6.2
Publication..........................................................................................57
11
References Cited in the Text...............................................................58
12
Appendices .........................................................................................59
Appendix I
Signature Pages and Responsible Persons for the Trial......................59
Signature Page – Protocol Lead.........................................................................................60
Signature Page – Principal Investigator.............................................................................61
Sponsor Responsible Persons not Named on the Cover Page ...........................................62
Appendix II
Blood Volume Sampled in the Clinical Trial .....................................63
Appendix III
Contraception Guidance .....................................................................64
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Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
6/65
Table of In-Text Tables
Table 1
Schedule of Assessments....................................................................13
Table 2
Clinical Laboratory Evaluations.........................................................44
Table 3
Time Windows....................................................................................46
Table 4
Definition of PK Parameters for Tepotinib and its Metabolites 
After Single Dose Administration ......................................................47
Table 5
Overview of the PK-Variability Observed in Tepotinib Study 
MS200095-0044 .................................................................................49
Table of In-Text Figures
Figure 1
Overall Trial Design ...........................................................................20
Figure 2
Design of the Trial..............................................................................20
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Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
7/65
List of Abbreviations
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
ALU
Aluminum
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration-time curve
AUC0-∞
Area under the plasma concentration-time curve from time zero (= dosing 
time) extrapolated to infinity
AUC0-t
Area under the plasma concentration-time curve from time zero (= dosing 
time) to the last sampling time (tlast) at which the concentration is at or above 
the lower limit of quantification.
AUCextra
The AUC from time tlast extrapolated to infinity
AUCextra%
AUCextra / AUC0-∞in percent
beta-HCG
Beta-human chorionic gonadotropine
BMI
Body mass index
CI
Confidence interval
CK-MB
Creatine phosphokinase - myocardium/brain type
CL/f
Apparent total body clearance considering the fraction of dose (f) absorbed
Cmax
Maximum plasma concentration
c-Met
Mesenchymal-epithelial transition factor
CRO
Contract research organization
CTCAE
Common Terminology Criteria for AEs
CV
Coefficient of variation
ECG
Electrocardiogram
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
EMA
European Medicines Agency
EudraCT
European Union Clinical Trials Register
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GeoMean
Geometric mean 
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Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
8/65
GMR
Geometric Mean Ratio
h
Hour(s)
HCC
Hepatocellular carcinoma
HGF
Hepatocyte growth factor
HIV1/HIV2
Human immunodeficiency virus 1 and 2
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation 
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
LLOQ
Lower limit of quantification
min
Minute(s)
NCI
National Cancer Institute
NSCLC
Non-small cell lung cancer
PGx
Pharmacogenetics
PK
Pharmacokinetics
QTcF
Corrected QT interval according to Fridericia
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SD
Standard deviation
SUSAR
Suspected unexpected serious adverse reactions
T/R
Test/Reference
t1/2
Terminal half-life
TEAE
Treatment emergent adverse event
TF1; TF2; TF3
Tablet Formulation 1; Tablet Formulation 2; Tablet Formulation 3
tlast
The last sampling time at which the concentration is at or above the lower 
limit of quantification
tmax
Time to reach the maximum plasma concentration
ULN
Upper limit of normal range
VZ/f
Apparent volume of distribution during terminal phase (after 
oral/extravascular administration)
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Te p oti ni b ( M S C 2 1 5 6 1 1 9 J)
Bi oe q ui v ale nce of 5 t a blets of 1 0 0 m g vs 2 t a blets of  25 0 m g T F 3 of 
te p oti ni b
M S 2 0 0 0 9 5 _ 0 0 3 8
C O N F I D E N T I A L
I N F O R M A T I O N
9/ 6 5
1
S y n o psis
Cli nic al Tri al Pr ot oc ol N u m ber
M S 2 0 0 0 9 5 _ 0 0 3 8
Title
A n o pe n -la bel, si n gle-d ose, ra n d o mize d, 
2 peri o d, 2 -se q ue nce cr oss-o ver, si n gle -ce nter 
P hase I trial i n healt h y s u bjects t o assess t he 
bi oe q ui vale nce of te p oti ni b ta blet f or m ulati o n 3 
a d mi nistere d as 5 ta blets of 1 0 0 m g vers us 
2 t a blets of 2 5 0 m g d ose stre n gt h.
Tri al P h ase
1
I N D N u m ber
N ot a p plica ble
F D A c o vere d tri al
N o
E u dr a C T N u m ber
2 0 1 9- 0 0 3 5 7 8- 1 3
Pri nci p al I n vesti g at or
 
 Ger ma n y
S p o ns or
Merc k Healt hcare K Ga A, 
a n affiliate of Merc k K Ga A, Dar msta dt, 
Ger ma n y,
Fra n kf urter Strasse 2 5 0, 
6 4 2 9 3 Dar msta dt, Ger ma n y
Tri al ce nter
 
 Ger ma n y 
Pl a n ne d tri al peri o d
(first s u bject i n-l ast s u bject o ut)
Oct o ber t o Dece m ber 2 0 1 9
Tri al Re gistr y
Cli nical Trial. g o v, E U Cli nical Trials Re gister
Pri m ar y O bjecti ves:

T o de m o nstrate bi oe q ui vale nce bet wee n 5 ta blets of t he 1 0 0 m g d ose stre n gt h of te p oti ni b
ta blet f or m ulati o n 3 ( T F 3, test treat me nt) a n d 2 ta blets of t he 2 5 0 m g  d ose stre n gt h of T F 3 
(refere nce treat me nt) after si n gle d os e a d mi nistrati o n i n healt h y  su bjects u n der fasti n g 
c o n diti o ns
Sec o n d ar y O bjecti ves:

T o f urt her i n vesti gate t he P K of te p oti ni b
D oc u me nt N o. 0 9 0 0 ba be 8 1 2c d 5a 9 v 1. 0
O bject N o. 0 9 0 0 ba be 8 1 2 d 9 4 8a
Pa ge 1 0 of 6 6
PI
PI
PI


Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
10/65
To further assess the safety and tolerability of tepotinib TF3 under fasting conditions
Exploratory Objectives:
To investigate the PK of tepotinib metabolites 
To explore the effect of pharmacogenetics (PGx) and variations of associated genes on the 
PK profile of tepotinib (if applicable).
Methodology: This is an open-label, single-dose, randomized, 2-period, 2-sequence 
cross-over, single-center trial to investigate the bioequivalence of the 100 mg and 250 mg dose 
strengths of tepotinib tablet formulation 3 under fasted condition.
For each subject, the study consists of a screening period (Day -21 to Day -2) and 2 treatment 
periods including a washout of 21-days in each period. Eligible subjects will be admitted to the 
clinical unit on Day -1. Subjects who continue to meet the eligibility criteria will be randomized 
to 1 of 2 treatment sequences on Day 1 of Period 1. 
In each study period, the subjects will be hospitalized from Day -1 to Day 4 for safety 
assessments and PK blood sampling and return to the site on Days 5 - 8 for additional PK blood 
sampling and monitoring of AEs and concomitant medication. Study drug will be administered 
on Day 1 of each period. An End of Trial Visit will be performed at the end of Period 2 (21 days 
after dosing in Period 2).
Planned number of subjects: 
18 subjects.
Primary Endpoints:
Area under the plasma concentration-time curve (AUC) from time zero (= dosing time) to 
the last sampling time at which the concentration is at or above the lower limit of 
quantification (AUC0-t), AUC from time zero extrapolated to infinity (AUC0-∞) and 
maximum plasma concentration (Cmax) of tepotinib observed from time zero to 168 h post-
dose of each period.
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Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
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MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
11/65
Secondary Endpoints:
Time to reach Cmax (tmax), terminal half-life (t1/2), apparent total body clearance considering 
the fraction of dose absorbed (CL/f) and apparent volume of distribution during terminal 
phase (Vz/f) of tepotinib observed from time zero to 168 h post-dose of each period
Occurrence of treatment-emergent adverse events (TEAEs; incidence, frequency, intensity 
and causality), occurrence of changes in safety laboratory assessments, 12-lead 
electrocardiograms (ECGs) and vital signs.
Exploratory Endpoints:
PK profiles of tepotinib metabolites: 
AUC0-t, AUC0-∞, Cmax, tmax, t1/2 of tepotinib metabolites observed from time zero to 168 h 
post-dose of each period
Genetic variants and mutations in genes that potentially influence PK of tepotinib.
Pharmacokinetics:
Plasma concentrations of tepotinib and its metabolites MSC2571109A and MSC2571107A 
will be determined in each study period from pre-dose until 168 h post-dose. PK parameters 
will be calculated using non-compartmental analysis.
Pharmacogenetics: PGx analysis on Day -1 of Period 1
Other assessments: Not applicable
Diagnosis and key inclusion and exclusion criteria:
Healthy males and females (of non-childbearing potential) between 18 to 55 years (inclusive) 
with a body mass index (BMI) ≥18.5 and ≤29.9 kg/m2 and a total body weight between 50 
and 100 kg (inclusive) at the time of Screening examination may be enrolled in the trial.
Investigational Medicinal Product: dose/mode of administration/ dosing schedule:
Tepotinib film-coated tablet TF3 containing 100 mg of drug substance for oral 
administration (test treatment)
Tepotinib film-coated tablet TF3 containing 250 mg of drug substance for oral 
administration (reference treatment)
Administration of single doses of 500 mg tepotinib per treatment period, administered as 
2 tablets of 250 mg, and 5 tablets of 100 mg, after overnight fasting.
The washout period between single doses will be at least 21 days.
Reference therapy: dose/mode of administration/dosing schedule: Not applicable
Planned trial and treatment duration per subject: 
About 9 weeks each from Screening to End of Trial Visit, including 2 treatment periods of 
21 days each.
Statistical methods:
Primary Endpoints: 
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Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
12/65
An analysis of variance (ANOVA) model will be fitted to the log-transformed PK parameters 
Cmax, AUC0-t, AUC0-∞based on the PK analysis set. The model will include treatment, period, 
sequence as fixed effects and subject within sequence as random effect. 
Treatment differences on the log scale of tepotinib will be estimated for Cmax, AUC0-t, AUC0-∞
together with their 90% CIs. 
The null hypothesis of non-bioequivalence will be rejected if the 90% CI for the ratio of the 
geometric mean lies within the bioequivalence acceptance interval of 0.8000 to 1.2500 for all 
primary PK parameters. 
Secondary and exploratory endpoints will be analyzed with summary statistics.
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Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
13/65
Table 1
Schedule of Assessments
Assessment/ Activity
Screening
All periods
End of Trial Visit
Day
-21 to -2
-1
1
2 - 4
5 - 8
21 (± 1) after dosing in Period 2
Written informed consent a
Hospitalization
X ----------------------------------------------------------------- X
Ambulatory visits
X
X
X
In-/exclusion criteria
X
X (Period 1 only)
Randomization
X (predose, 
Period 1 only)
Demographic data (incl. height, weight, 
BMI)
X
Medical history
X
Physical examination
X
X
Day 2, Day 4 e
X
Vital signs (blood pressure, pulse rate, 
body temperature)
X
X
pre-dose, 2 h, 8 h
Day 2, Day 4 e
X
12-lead safety ECG
X
X
pre-dose b, 2 h, 
8 h
Day 2, Day 4 e
X
Clinical laboratory (hematology, 
biochemistry, urinalysis)
X
X
pre-dose
Day 2, Day 4 e
X
Coagulation
X
Serology (HIV/hepatitis)
X
Pregnancy test (in serum at Screening 
and End of Trial Visit, in urine on Day -1)
X
X
X
Urine drug screen; Alcohol breath test
X
X
Administration of tepotinib
X
PK blood sampling
X c
X c
X c
PGx blood sampling
X (Period 1 only)
Adverse events monitoring
X
X -----------------------------------------------------------------------------------------------------------------X d
(Prior and) concomitant medication
X
X -----------------------------------------------------------------------------------------------------------------X d
BMI = body mass index, ECG = electrocardiogram, h = hours, HIV = human immunodeficiency virus, min = minutes, PK = pharmacokinetics, 
PGx = pharmacogenetics
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Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
14/65
a
Written informed consent must be obtained prior to any screening activities 
b
ECGs at pre-dose will be recorded in triplicate
c
PK blood samples for determination of tepotinib and its metabolites will be collected at pre-dose (within 60 min prior to dosing) and 15, 30, 45, 60, 90 min, 
and 2, 3, 4, 6, 8, 12, 16 and (Day 2) 24, 36, (Day 3) 48, 60, (Day 4) 72, (Day 5) 96, (Day 6) 120, (Day 7) 144 and (Day 8) 168 h post-dose
d
Adverse events and concomitant medication will be assessed from signing of the informed consent form throughout the whole study until End of Trial.
e
All safety assessments on Day 4 before discharge.
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Te p oti ni b ( M S C 2 1 5 6 1 1 9 J)
Bi oe q ui v ale nce of 5 t a blets of 1 0 0 m g vs 2 t a blets of  25 0 m g T F 3 of 
te p oti ni b
M S 2 0 0 0 9 5 _ 0 0 3 8
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 /6 5
2
S p o ns or, I n vesti g at ors a n d Tri al A d mi nistr ati ve Str uct ure
T his cli nical trial will be s p o ns ore d b y:  
Merc k Healt hcare K Ga A a n affiliate of Merc k K Ga A, Fra n kf urter Strasse 2 5 0, 6 4 2 9 3 Dar msta dt, 
Ger ma n y.
Si n gle trial site at 
, Ger ma ny.
T he Pri nci pal I n vesti gat or (
, 
 
, Ger ma n y) will pr o vi de e x pert me dical i n p ut a n d a d vice relati n g t o trial desi g n a n d 
e xec uti o n a n d is res p o nsi ble f or t he re vie w a n d si g n off of t he cli nical trial re p ort c o nsiste nt wit h 
t he I nter nati o nal C o u ncil f or Har m o nisati o n (I C H) T o pic E 6 G o o d Cli nical Practice ( G C P; 
hereafter referre d t o as I C H G C P) [7 ]. 
Si g nat ure pa ges f or t he Pr ot oc ol Lea d a n d t he Pri nci pal I nvesti gat or as well as a list of S p o ns or 
res p o nsi ble pers o ns are i n A p pe n di x I .
T he trial will a p pear i n t he f oll o wi n g cli nical trial re gistries: E ur o pea n U ni o n Cli nical Trials 
Re gister ( E u dra C T), Cli nical Trials. g o v.
N u visa n G m b H, We ge nerstrasse 1 3, 8 9 2 3 1 Ne u -Ul m, Ger ma n y , a c o ntract researc h or ga nizati o n 
( C R O), will co n d uct t he cli nical part of t he trial i ncl u di n g trial set- u p, c o or di nati o n, safety a n d 
a nal yt ical la b, m o nit ori n g, data ca pt ure, data ma na ge me nt, statistical a nal ysis, a n d cli nical trial 
re p orti n g. N u visa n 
G m b H 
will 
als o s u b mit t he necessar y  ap plicati o ns t o t he a p plica ble 
I n de pe n de nt Et hics C o m mittee (I E C) a n d re g ulat or y bo dies o n be half of a n d i n cl ose ali g n me nt 
wit h t he S p o ns or. 
La b orat or y  sa m ple pr ocessi n g, ha n dli n g, a n d st ora ge i nstr ucti o ns will be prese nte d i n a se parate 
La b Ma n ual 
w hic h will be pre pa re d b y  Nu visa n G m b H i n c o o perati o n wit h t he S p o ns or. 
M o nit ori n g a n d data ma na ge me nt pr oce d ures will be defi ne d i n se parate M o nit ori n g a n d Data 
Ma na ge me nt Pla ns w hic h will be pre pare d b y N u visa n G m b H.
T he S p o ns or will pr o vi de t he I n vesti gati o nal Me dici nal P r o d uct (I M Ps) te p oti ni b. Pac ka gi n g, 
la beli n g a n d distri b uti o n of all I M Ps t o t he trial site will be c o n d ucte d b y  a desi g nate d c o ntract 
ma n ufact uri n g 
or ga nizati o n ( N u visa n G m b H). 
T he S p o ns or will 
s u per vise all o uts o urce d 
acti vities.
3
B ac k gr o u n d I nf or m ati o n
T he mese nc h y m al -e pit helial tra nsiti o n fact or (c-Met), al o n g wit h its li ga n d, t he he pat oc y te gr o wt h 
fact or ( H G F) ha ve bee n i m plicate d i n carci n o ge nesis a n d metastatic t u m or pr o gressi o n, beca use 
of t heir a bilit y t o e n ha nce a n gi o ge nesis, ca ncer cell pr oliferat i o n, mi grati o n a n d i n vasi o n, as well 
D oc u me nt N o. 0 9 0 0 ba be 8 1 2c d 5a 9 v 1. 0
O bject N o. 0 9 0 0 ba be 8 1 2 d 9 4 8a
Pa ge 1 6 of 6 6
PI
PI
PI


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as conferring resistance to apoptosis. Pharmacological interference with the HGF/c-Met axis is 
considered as a promising strategy to inhibit primary tumor growth and metastasis.
In primary pharmacodynamic studies, tepotinib (MSC2156119J) potently inhibited c-Met kinase 
activity in a dose-dependent manner. This inhibitory effect was confirmed both in tumor cells 
expressing full-length c-Met upon stimulation with HGF, and in tumor cells in which c-Met was 
activated in a ligand independent manner, ie in cells harboring c-Met gene amplification or 
expressing the oncogenic fusion protein translocated promoter region (TPR) Met.
Until 19-July-2019, 715 subjects have been exposed to tepotinib at doses up to 1400 mg, including 
195 healthy participants, and 12 subjects with Child-Pugh class A or B hepatic impairment in 8 
Clinical Pharmacology studies.
Four of the Clinical Pharmacology studies in healthy subjects (EMR200095-007, n = 27;
EMR200095-0012, n = 24; MS200095-0039, n = 12 and MS200095-0044, n = 66) were 
conducted as single-dose studies with 500 mg tepotinib, in one study (EMR200095-002, n = 28), 
single doses of 30 mg tepotinib were administered to healthy subjects. In two further studies, 
healthy subjects received multiple doses of 500 mg tepotinib over 11 days (MS200095-0030, 
n = 12) or 8 days (MS200095-0032, n = 20).
In all 7 studies performed in healthy subjects, the subjects well tolerated single doses of 30 mg or 
500 mg tepotinib, or multiple doses of 500 mg tepotinib. All treatment-emergent adverse events 
(TEAEs) were mild to moderate, except 2 Grade 3 asymptomatic lipase elevations in 2 subjects, 
and 2 Grade 3 TEAE (back pain and collum femoris fracture) that were not considered related to 
treatment. TEAEs did not show a pattern across the trials. No drug-related serious adverse events 
(SAEs) were reported and no subject died. No clinically significant findings regarding laboratory 
parameters, vital signs and electrocardiogram (ECG) including corrected QT interval according to 
Fridericia (QTcF) were noted.
In a further Clinical Pharmacology trial (MS200095-0028), 6 subjects with Child-Pugh Class A, 6 
subjects with Class B hepatic impairment, and 6 healthy subjects received single doses of 500 mg 
tepotinib. No subject had serious adverse events, Grade ≥ 3 TEAEs, or discontinued due to a 
TEAE, or died during the study
In 2 clinical studies (EMR200095-001 and EMR200095-003), 161 patients with different solid 
tumors received multiple doses up to 1400 mg tepotinib. In 2 studies, 138 patients with 
hepatocellular cancer (EMR200095-004 and EMR200095-005) received multiple doses of 
300 mg, 500 mg or 1000 mg tepotinib. In a clinical study in patients with MET-positive, non-
small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor mutations 
(EMR200095-006), 64 patients received multiple doses of 300 mg or 500 mg tepotinib.
Until 19-July-2019, 145 patients with NSCLC in the ongoing VISION trial (MS200095-0022) 
have received multiple doses of 500 mg tepotinib.
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Elevations in serum lipase and amylase are identified risks for tepotinib and were observed in 
healthy subjects and patients exposed to tepotinib. These increases were mild to moderate in 
severity (exception: 1 Grade 3 lipase elevation), transient and without apparent dose dependency. 
All increases of serum amylase/lipase were asymptomatic and not associated with pancreatitis. 
This study will investigate the bioequivalence of tepotinib tablet formulation 3 (TF3) administered 
as 5 tablets of 100 mg versus 2 tablets of 250 mg dose strength. A dose of 500 mg once daily is 
the recommended Phase 2 dose. Refer to the Investigator’s Brochure (IB) for further information 
about the nonclinical and clinical programs and the implemented Guidance for the Investigator.
For the PK of tepotinib refer to the IB.
3.1
Trial Rationale
This trial will investigate the bioequivalence of the 100 mg dose strength (test treatment) of the 
envisioned market formulation, TF3, compared to the 250 mg dose strength of the same 
formulation (reference treatment), both given at a single dose of 500 mg. The 250 mg dose strength 
of TF3 had been shown to be bioequivalent to the 500 mg dose strength of TF2, used in the Phase 2 
studies, and in a previous bioequivalence study (MS200095-0044).
While the recommended clinical dose of 500 mg for the treatment of patients with NSCLC can be 
administered using the 250 mg dose strength, the lower TF3 dose strength of 100 mg will be made 
available for individual dose adaptation and future development options.
The tablet cores of both TF3 dose strengths are identical. The tablet film-coating is a 
non-functional coating that differs only marginally in composition between both dose strengths.
However, owing to the different tablet sizes, the difference of coating material per surface area 
formally exceeds regulatory thresholds in certain regulatory regions. Clinical investigation of 
bioequivalence between the TF3 strengths will therefore be performed.
The trial design using an open-label 2-period, 2-sequence cross-over design under fasted 
conditions follows the regulatory guidelines of the Food and Drug Administration (FDA) [1, 2], 
the European Medicines Agency (EMA) [3] and the Pharmaceuticals and Medical Devices Agency 
(PMDA) [4, 5].
This clinical trial will be conducted in compliance with the clinical trial protocol, ICH GCP [7], 
and any additional applicable regulatory requirements.
Based on the available nonclinical and clinical data to date, the conduct of the trial specified in 
this protocol is considered justifiable.
3.2
Risk/Benefit Assessment
Based on the currently available nonclinical as well as clinical safety data, and the lack of 
genotoxicity in non-clinical studies, there is no objection against administration of single doses of 
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tepotinib to healthy subjects. It is recognized that healthy subjects will not get benefit by 
participating in this study. Subjects enrolled in this study might be exposed to a potential risk, 
including pancreatic enzyme elevation. However, inclusion of healthy subjects is justified when 
the administration of tepotinib is limited to a single dose or short-term multiple administrations 
that will be given under close monitoring conditions to reduce the risk for untoward effects.
Since loss of c-Met induces teratogenic effects in c-Met knockout mice, and since a pilot embryo-
fetal development study in rabbits revealed maternotoxic effects and a dose-dependent increased 
number of skeletal malformations (teratogenicity), stringent criteria are applied to ensure exclusion 
of women of childbearing potential in this study. Only healthy women that are known to be 
postmenopausal or surgically sterile (ie due to hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy) will be enrolled in this study (for details see Section 5.3.1). Male subjects will be 
required to take precautions with regards to female partners. 
To further mitigate any risk, a close monitoring of the safety laboratory parameters, ECG, and vital 
signs will be performed in all healthy subjects. Subjects will be admitted to the study site and 
remain resident there for at least 72 h after administration of a single dose in each treatment period, 
to allow continuous safety monitoring. In addition, frequent monitoring of subjects is ensured by 
subsequent ambulant visits and by choosing a CRO experienced in the conduct of clinical 
pharmacology studies.
In summary, healthy subjects will be included in the study to minimize variability, which is 
expected to be higher in a patient population. Non-clinical safety investigations did not reveal a 
genotoxicity potential or other findings with relevance for human use. Therefore, it is reasonable 
that tepotinib can be administered to healthy subjects such as in this study in which careful safety 
monitoring is conducted. Knowing that tepotinib shows teratogenic effects, only healthy women 
who are postmenopausal or surgically sterile (ie, due to hysterectomy, or bilateral oophorectomy, 
or bilateral salpingectomy) will be enrolled in this study and male subjects must and have their 
female partner of childbearing potential use methods of highly effective contraception.
4
Trial Objectives
4.1
Primary Objectives
To demonstrate bioequivalence between 5 tablets of the 100 mg dose strength of tepotinib TF3 
(test treatment) and 2 tablets of the 250 mg dose strength of TF3 (reference treatment) after 
single dose administration in healthy subjects under fasting conditions.
4.2
Secondary Objectives
To further investigate the PK of tepotinib.
To further assess the safety and tolerability of tepotinib TF3 under fasting conditions.
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4.3
Exploratory Objectives
To investigate the PK of tepotinib metabolites
To explore the effect of pharmacogenetics (PGx) and variations of associated genes on the PK
profile of tepotinib (if applicable).
5
Investigational Plan
5.1
Overall Trial Design and Plan
This is an open-label, single-dose, randomized, 2-period, 2-sequence cross-over, single-center trial 
to investigate the bioequivalence of the 100 mg and 250 mg dose strengths of tepotinib TF3 when 
administered at the same dose under fasted condition.
For each subject, the study consists of a screening period (Day -21 to Day -2) and 2 treatment 
periods, including a 21-days washout in each period. Eligible subjects will be admitted to the 
clinical unit on Day -1. Subjects who continue to meet the eligibility criteria will be randomized 
to 1 of 2 treatment sequences on Day 1 of Period 1. 
In each study period, the subjects will be hospitalized from Day -1 to Day 4 for safety assessments 
and PK blood sampling and return to the site on Days 5 - 8 for additional PK blood sampling and 
monitoring of AEs and concomitant medication. Study drug will be administered on Day 1 of each 
period. An End of Trial Visit will be performed at the end of Period 2 (21 days after dosing in 
Period 2).
More details are given in Section 7.1. 
Common Visit Schedule
Trial procedures are the same for both periods. 
The washout period will be at least 21 days between Day 1 of each period (see Figure 2).
A screening period is implemented from Day -21 to Day -2.
Subjects will be admitted to the study site on Day -1 of each period and will be resident at the 
study site under medical supervision from Days -1 to 4. They must visit the site on the morning of 
Days 5 to 8 for further blood sampling. 
Blood and urine samples will be collected for laboratory assessments (hematology, biochemistry, 
urinalysis), which will be performed at Screening, throughout the in-patient period of each 
treatment period and for the End of Trial Visit. 
Serial blood samples for PK assessments will be collected for 168 h after tepotinib administration 
in all periods. 
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The End of Trial Visit is planned 21 days (± 1 day) after tepotinib administration in the second 
period. An Early Termination Visit will be conducted for subjects who withdraw prematurely. The 
same assessments as for the End of Trial Visit will be conducted at the Early Termination Visit.
Figure 1
Overall Trial Design
Test treatment: 5 tablets 100 mg tepotinib TF3, Reference treatment: 2 tablets 250 mg tepotinib TF3
Figure 2
Design of the Trial
Each Period
Day
Procedure
-1
1
2 to 4
5 to 8
21
Hospitalization
Tepotinib administration
PK blood sampling
Safety assessmentsa
AE monitoring
AE = adverse event, PK = pharmacokinetics
The washout period will be at least 21 days between Day 1 of each period.
a Safety assessments: Vital signs, 12-lead electrocardiogram, clinical laboratory during hospitalization and at the End 
of Trial Visit.
A detailed schedule of study procedures and assessments is provided in Table 1.
5.2
Discussion of Trial Design
The primary objective is to demonstrate bioequivalence between 5 tablets of the 100 mg dose 
strength of TF3 (test treatment) and 2 tablets of the 250 mg dose strength of TF3 (reference 
treatment) after single dose administration in healthy subjects under fasting conditions.
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The general trial design is strictly based on the regulatory guidelines of the FDA [1, 2], EMA [3] 
and PMDA [4, 5].
5.2.1
Inclusion of Special Populations
Not applicable.
5.2.2
Scientific Rationale for Trial Design
The trial design and endpoints are typical for bioequivalence studies of this type. The single dose 
design under fasted conditions is more sensitive in showing changes in the PK as compared to 
multiple dose designs and is generally recommended by the relevant guidelines [1-5].
As illustrated in Figure 1, the study will utilize a randomized open-label, 2-period, 2-sequence 
cross-over design to minimize the influence of covariates. 
In a recent clinical study with PK sampling up to 504 h after administration (MS200095-012), 
terminal elimination half-lives (t1/2) of about 30 h for the parent compound tepotinib and about 
45 h for the main metabolites MSC2571109A and MSC2571107A were observed (Study 
MS200095-0012). Due to the very sensitive bioanalytical method, very low concentrations (< 5% 
of the maximum plasma concentration [Cmax]) were observed after 14 days in study MS200095-
0012. No (or only negligible) concentrations above the detection limit are expected after 21 days 
following dosing. Accordingly, the washout period will be at least 21 days between Day 1 (study 
drug administration) of each treatment period to further minimize potential carry-over.
In a previous clinical study with single-dose administrations of 500 mg tepotinib as TF3 under 
fasted conditions (EMR200095-0044, Part A), the median time to reach the maximum plasma 
concentration (tmax) was 12 h (ranging from 8 h to 36 h), and the mean apparent half-life was 30.9 h 
(95% confidence interval: 29.4 h to 32.5 h). The PK sampling scheme (see Table 1) with sampling 
up to 168 h after administration is expected to adequately cover the absorption, distribution and 
elimination phases up to > 80% of the AUC from time zero (dosing time) extrapolated to infinity 
(AUC0-∞).
This trial will be performed in healthy volunteers to standardize the trial population and minimize 
inter-subject variability. 
5.2.3
Justification for Dose
The 500 mg single oral dose has been studied in previous studies in healthy subjects and was found 
to be safe and well tolerated. The tepotinib dose of 500 mg is the recommended Phase 2 dose
(RP2D) for the treatment of human malignant tumors.
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5.2.4
Rationale for Endpoints
The peak (Cmax) and extent (area under the plasma concentration-time curve [AUC0-t and AUC0-∞
]) of exposure after single dose administration are considered adequate endpoints to evaluate the 
bioequivalence. These endpoints are in line with the regulatory guidance of the FDA, EMA and 
PMDA (see Section 3.1).
5.3
Selection of Trial Population
Only persons meeting all inclusion criteria and no exclusion criteria may be enrolled into the trial 
as subjects. Prior to performing any trial assessments not part of the subject’s routine medical care, 
the Investigator will ensure that the subject has provided written informed consent following the 
procedure described in Section 9.2.
5.3.1
Inclusion Criteria
To be eligible, the subject must fulfill all the following criteria:
1.
Male or female, aged 18 to 55 years inclusive (at Screening)
2.
Body mass index (BMI) ≥18.5 and ≤29.9 kg/m2 and body weight between 50 and 100 kg, 
inclusive (at Screening)
3.
A female participant is eligible to participate if she is not pregnant, not breastfeeding and of 
non-childbearing potential, confirmed at Screening, by fulfilling at least 1 of the following 
criteria (Appendix III
Contraception Guidance): 
Females who are postmenopausal (age-related amenorrhea ≥12 consecutive months and 
increased follicle-stimulating hormone [FSH] > 40 mIU/mL)
Documentation of irreversible surgical sterilization by hysterectomy, bilateral 
oophorectomy, or bilateral salpingectomy
4.
A male participant must agree to use and to have his female partner of childbearing potential 
to use highly effective methods of contraception (ie methods with a failure rate of less than 
1% per year) as detailed in the Clinical Trial Facilitation Group (CTFG) recommendations 
[6] during the period of participation in the study and for at least 3 months after the last IMP 
administration (see Appendix III). Males must also refrain from donating sperm during this 
period and should always use a barrier method such as condom concomitantly. The male 
participants will be asked to report pregnancies in their female partners up to 3 months after 
the last IMP intake.
5.
Subject must be healthy, as assessed by the Investigator, with no clinically significant 
abnormality identified on physical examination and no active clinically significant disorder, 
condition, infection or disease that would pose a risk to subject safety or interfere with the 
study evaluation, procedures, or completion (at Screening and Day -1).
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6.
Subject must have given written informed consent before any study-related activities are 
carried out and must be able to understand the full nature and purpose of the study, including 
possible risks and adverse effects. 
7.
All values for hematology, coagulation, and biochemistry tests of blood and urinalysis within 
the normal range (at Screening). Minor (solitary) non-clinically relevant deviation(s) are 
allowed as judged by the Investigator, however amylase and lipase should not exceed the 
upper limit of normal range (ULN); alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) should not exceed the ULN x 1.1.
5.3.2
Exclusion Criteria
Subjects are not eligible for this study if they fulfill any of the following exclusion criteria:
1.
Participation in the treatment phase of a clinical study within 60 days or 5 half-lives after last 
dosing of the previous study drug, whatever is longer, before administration of study drug
2.
Whole blood donation or loss of > 450 mL within 60 days before administration of study drug
3.
Any surgical or medical condition, including findings in the medical history or in the pre-
study assessments, or any other significant disease, that in the opinion of the Investigator, 
constitutes a risk or a contraindication for the participation of the subject in the study or that 
could interfere with the study objectives, conduct, or evaluation
4.
Supine systolic blood pressure > 140 or < 90 mmHg, diastolic blood pressure > 90 or 
< 50 mmHg, and pulse rate > 90 or < 50 beats per minute (min) at Screening and at Admission 
on Day -1 (Any abnormal blood pressure results may be repeated once and if the repeat result 
is within the normal range, it is not considered to have met the exclusion criterion)
5.
12-Lead ECG showing a QTcF > 450 ms, PR > 215 ms, or QRS > 120 ms 
6.
Creatinine clearance estimated glomerular filtration rate (eGFR) < 90 mL/min as assessed by 
using the estimated measure with the Cockcroft-Gault equation (at Screening). In case of a 
borderline result between ≥80 and 90 mL/min, Cystatin C will be determined in addition, and 
the subject will only be included if the Cystatin C value is below the ULN. 
7.
Subjects with gall bladder removal or other relevant surgery of gastrointestinal tract. 
(Appendectomy is not considered as relevant)
8.
History of any malignancy except for adequately treated superficial basal cell carcinoma 
9.
History of epilepsy
10. Ascertained or presumptive allergy/hypersensitivity to the active drug substance and/or 
excipients; history of anaphylaxis to drugs or serious allergic reactions leading to 
hospitalization or any other allergy reaction in general, which the Investigator considers may 
affect the safety of the subject and/or outcome of the study
11. Positive screen for alcohol and drugs of abuse (at Screening and Day -1 of Period 1) 
12. Positive screen for hepatitis B surface antigen, hepatitis C virus antibody, and human 
immunodeficiency virus 1 and 2 antibodies (HIV1/HIV2 antibodies) (at Screening)
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13. Excessive consumption of xanthine-containing food or beverages (> 5 cups of coffee or 
equivalent a day) or inability to stop consuming caffeine (at Screening and Day -1)
14. Receipt of any prescription or nonprescription medication within 14 days or 5 half-lives, 
whatever is longer, before study drug administration (apart from paracetamol up to 1500 mg 
per day, as judged appropriate by the Investigator)
15. Smoker (cigarettes, pipes, cigars, or others) or former smoker who stopped smoking for less 
than 6 months before the time of the Screening Visit
16. Intake of grapefruit, Seville orange, cranberry or juices of these fruits, or St John’s Wort, from 
14 days prior to Day -1 of Period 1
17. Inability to communicate or cooperate with the Investigator (eg, language problem, illiteracy, 
poor mental status) or to comply with the requirements of the entire study, including dietary 
restrictions 
18. Other factors, which in the opinion of the Investigator may interfere with study conduct (at 
Screening and Day -1 of Period 1 only)
19. Legal incapacity or limited legal capacity
20. Subjects kept in detention
5.4
Criteria for Initiation of Trial Treatment
Inclusion and exclusion criteria will be checked within the screening period and again on Day -1 
of Period 1. Subjects meeting all the inclusion and none of the exclusion criteria will be 
randomized to a treatment sequence on Day 1 of the first treatment period.
5.5
Criteria for Subject Withdrawal
5.5.1
Withdrawal from Trial Therapy 
A subject must be withdrawn from IMP administration if any of the following occur:
The subject requires treatment with any medication suspected or known to interfere with the 
IMP 
The subject is suspected or known not to comply with the protocol directives (use of prohibited 
medication, noncompliance with the sampling schedule, nonadherence to dietary rules, and 
nonattendance at study assessments).
Withdrawal of a subject from study drug due to any of the above reasons means that this subject 
prematurely discontinues the study, ie before completion of the full profiling and all safety 
investigations. Subjects who dropped out, must be encouraged to attend the End of Trial 
examination for safety reasons (see Table 1).
Subjects who dropped out will not be replaced as per design specificity. A drop-out compensation 
of 2 subjects has been added. 
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5.5.2
Withdrawal from the Trial
Subjects must be withdrawn from the trial by the Investigator at any time for any of the following 
reasons:
Subject withdrew consent
Subject lost to Follow-up
Participation in another clinical study 
Relevant adverse events (AEs), especially SAEs, occur that do not justify the subject’s 
continuation in the study
Pregnancy
Protocol noncompliance judged as significant by the Investigator and/or Sponsor
Use of a non-permitted concomitant drug as defined in Section 6.5.2. However, any medications 
that are considered necessary for the subject’s well-being (eg paracetamol up to 1500 mg per 
day) may be given at the discretion of the Investigator
Subject is no longer able to participate for other medical reasons (eg surgery, intercurrent 
illness)
Any other condition which to the opinion of the Investigator no longer justifies or permits a 
safe participation of the subject
Any of the following individual stopping criteria is met unless deemed unrelated to the IMP by 
the Investigator with alternate etiology identified:
o Abnormal clinically relevant vital signs confirmed on 2 or more measurements 
(minimum 5 min intervals), including abnormal blood pressure 
-
hypotension defined as systolic < 80 mmHg and/or diastolic < 40 mmHg, or
-
hypertension defined as systolic > 160 mmHg and/or diastolic > 100 mmHg 
o Abnormal clinically relevant ECG findings, including a corrected QT-interval (ad modus 
Fridericia; QTcF) > 500 ms or an increase in QTcF > 60 ms compared to baseline, confirmed 
on ≥2 repeat measurements
o Marked increases in liver or renal parameters (ALT/AST ≥3 x ULN, total bilirubin ≥2 x 
ULN, creatinine ˃ 1.5 x ULN confirmed by ≥2 repeat measurements
o Any clinically relevant symptom or sign which in the opinion of the investigator and/or 
sponsor warrants subject withdrawal.
If a subject has failed to attend scheduled trial assessments, the Investigator must determine the 
reasons and the circumstances as completely and accurately as possible.
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In case a subject should be withdrawn from the trial, the medical monitor and clinical trial leader 
at the Sponsor will be informed immediately. If there is a medical reason for the withdrawal, 
appropriate medical care will be provided.
In case of premature withdrawal from the trial, the assessments scheduled for the last End of Trial 
Visit should be performed, as Early Termination Visit, if possible with focus on the most relevant 
assessments (see Table 1). In any case, the appropriate electronic case report form (eCRF) section 
must be completed.
Subjects who withdraw from the trial prior to the first administration of IMPs, or for any reason 
do not have a full PK dataset may be replaced. A discussion should occur between the Investigator 
and the Sponsor regarding whether a replacement may be considered.
5.6
Premature Termination of the Trial
The clinical trial may be terminated prematurely or suspended at the request of Health Authorities 
or if new safety or efficacy information leads to an unfavorable risk benefit judgment for any IMP. 
The Sponsor may discontinue the trial if it becomes unjustifiable for medical or ethical reasons, 
for poor enrolment, or because of discontinuation of clinical development of an IMP or withdrawal 
of an IMP or comparator from the market for safety reasons.
Health Authorities and IECs will be informed about the discontinuation of the trial in accordance 
with applicable regulations.
5.7
Definition of End of Trial
The End of Trial is defined as the last contact (related to this trial) with the last subject who 
participates in this study (last subject’s End of Trial Visit, independent of whether the subject is in 
End of Trial Visit or discontinued from the study).
A clinical trial protocol may not be considered closed as long as:
Any subject is still receiving any IMP
Visits specified by the protocol are still taking place
Procedures or interventions according to the protocol are still being undertaken in any subject 
The post-treatment follow up period, defined in the clinical trial protocol as being part of the 
trial, has not yet been completed for any subject.
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6
Investigational Medicinal Product and Other Drugs Used in 
the Trial
6.1
Description of the Investigational Medicinal Products
Investigational Medicinal Products: 
Tepotinib 
(MSC2156119J), 
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-
benzyl}-1,6-dihydro-6-oxo-pyridazin-3-yl)-benzonitrile hydrochloride hydrate (HCl), is supplied 
as
250 mg white-pink, oval, biconvex tablet with embossment “M” on one side TF3 for oral 
administration (reference treatment)
Tepotinib 250 mg film-coated tablets (TF3) have a drug load of approximately 30% and contain 
the excipients D-mannitol, microcrystalline cellulose, crospovidone, magnesium stearate, silica 
colloidal anhydrous, and Opadry® II pink.
100 mg white-yellow, round, biconvex tablets with embossment “M” on one side TF3 for oral 
administration (test treatment). 
Tepotinib 100 mg film-coated tablets (TF3) have a drug load of approximately 30% and contain 
the excipients D-mannitol, silica colloidal anhydrous, crospovidone, magnesium stearate, and 
Opadry II yellow.
All excipients used in the tablet formulations are of compendial grade. Supplier’s certificates show 
that there is no transmissible spongiform encephalopathy risk. Tepotinib is provided in aluminum 
(ALU/ALU) blisters and storage is at or below 25°C.
For dosage and administration see Section 6.2.
Reference product: Not applicable.
Specific rules for treatment modifications: Not applicable.
6.2
Dosage and Administration
In the two treatment periods, the subjects will receive the following single administrations of 
tepotinib in randomized order:
5 film-coated tablets TF3 containing 100 mg tepotinib, with a total dose of 500 mg (test 
treatment)
2 film-coated tablets TF3 containing 250 mg tepotinib, with a total dose of 500 mg (reference 
treatment)
Both treatments will be administered in the fasted state (after at least 10 h fasting) together with 
200 mL of water.
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The minimum washout period will be at least 21 days between Day 1 of each period to prevent 
any significant PK carryover effects between periods.
Subjects will be administered the tablet formulation in upright position. 
In both periods subjects will stay in a semi-recumbent position for 4 h post-dose, except for use of 
the toilet, when the subjects will be allowed to leave the bed without undue physical stress/activity.
Food intake is not allowed for 4 h after IMP administration. Further drinking is not allowed from 
1 h before to 1 h after IMP administration.
Standardized meals will be served approximately 4 h (lunch), 8 h (snack) and 10 h (dinner) after 
administration of tepotinib; thereafter, meals will be served at customary times during the in-
patient period.
6.3
Assignment to Treatment Groups
Only subjects who comply with all selection criteria will be included into the trial. Prior to the first 
administration, the subjects enrolled into the trial will be randomly assigned to 1 of 2 treatment 
sequences, via the random number on Day 1 of Period 1 (see Section 8.3).
According to CRO standard operational procedures (SOPs), the subjects will be assigned to the 
random number in the order of their registration to the study (first registration results in the lowest 
available random number, second registration results in the second lowest available random 
number, and so on). However, precedence will be given to subjects who participate in a trial at 
 for the first time and for subjects who served as “stand-by” during a preceding 
trial. 
The Investigator will keep a record relating the subjects’ random numbers and the names of all 
subjects (including screening number and the Nuvisan GmbH ID number) who have given their 
informed consent, to allow easy checking of data in subject files, when required. This record will 
also include the date of subject’s enrolment and completion, as well as subjects who could not be 
randomized for whatever reason.
6.4
Non-investigational Medicinal Products to be Used
Not applicable.
6.5
Concomitant Medications and Therapies
All concomitant medications taken by the subject during the trial, from the date of signature of 
informed consent are to be recorded in the appropriate section of the eCRF, noting the name, dose, 
route, duration, regimen, status and indication of each drug. Nondrug interventions and any 
changes to a concomitant medication or other intervention should also be recorded in the eCRF.
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6.5.1
Permitted Medicines
Paracetamol is the only permitted medication. Paracetamol will be permitted up to a maximum 
daily dosage of 1500 mg. 
Any medications that are considered necessary to protect subject welfare and that will not interfere 
with the IMP may be given at the Investigator’s discretion. The potential drug-drug interactions 
with tepotinib are still under evaluation. Therefore, medically required concomitant medication 
might have to be adjusted based on tolerability and the clinical response.
The Investigator will record, in the appropriate section of the eCRF, all previous/concomitant 
medications taken by the subject during the study from the date of signature of informed consent.
6.5.2
Prohibited Medicines
The subjects are prohibited from using prescription or over-the-counter medications (apart from 
paracetamol up to 1500 mg per day, as judged appropriate by the Investigator) within 14 days or 
5 half-lives, whichever is longer, prior to the first IMPs administration during the trial, and until 
after the End of Trial Visit.
6.5.3
Permitted / Prohibited Procedures
Subjects should drink about 2 L fluids per day during the hospitalization phase (as provided by the 
site) and will be reminded regularly.
Throughout the PK profiling day, the following restrictions must be met:
Subjects will be in the fasted state for at least 10 h before administration of tepotinib 
Drinking is not allowed 1 h before and after administration of tepotinib (except for the 
administration)
Chewing gum is not allowed during the PK profile days.
Throughout the study, the following restrictions must be met:
No smoking or use of tobacco products
No alcohol intake
No intake of food or beverages other than that provided to the subjects by the trial site during 
the in-patient period
No intake of caffeine- and xanthine-containing food and beverages (eg coffee, black or green 
tea, cola, cocoa, chocolate or chocolate-containing food or beverages) from 48 h before 
administration of tepotinib in each period until collection of last PK blood sampling of each 
period
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No intake of herbs or fruits that can have an influence on the PK (eg St. John’s wort, Seville 
oranges, grapefruits, cranberry or the juice of these fruits), from 14 days prior to Day -1 of 
Period 1 until final examination
No intake of poppy seeds (eg poppy seed rolls, poppy seed cake, yoghurt containing poppy seed 
etc.) from 72 h before first administration of study drug until completion of final examination
No intake of concomitant medication within 14 days or 5 half-lives, whatever is longer, before 
first administration of study drug until final examination (except for paracetamol up to 1500 mg 
per day, may be given at the discretion of the Investigator) 
No intake of recreational drugs within 14 days or 5 half-lives, whatever is longer, before first 
administration of study drug until final examination
No exhausting physical activities (body building, sports) from at least 72 h before the first 
administration of study drug until the final examination 
No sun baths, solarium, or sauna at least 12 h before first administration of study drug until 
final examination.
6.5.4
Other Interventions
Not applicable.
6.5.5
Special Precautions
Not applicable.
6.5.6
Management of Specific Adverse Events or Adverse Drug 
Reactions
No specific measures are proposed at this stage. Standard medical care will be provided at the 
study site for all AEs occurring during the study.
6.6
Packaging and Labeling of the Investigational Medicinal 
Product
All IMPs will be packaged and labeled in accordance with all applicable regulatory requirements 
and Good Manufacturing Practice Guidelines.
The investigational product tepotinib will be provided by the Sponsor packed in ALU/ALU blister.
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product
The pharmacy or designee will receive the IMPs labeled and packaged according to the local 
regulatory requirements and the storage requirements. Tepotinib will be supplied in ready to use 
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oral formulations. The responsible pharmacist will dispense the necessary amount of the IMPs. 
Detailed guidance will be provided in an IMP handling manual.
The IMP supplies will be recorded in an IMP inventory.
Tepotinib must be carefully stored at the trial site in a closed room or cabinet with restricted access, 
safely and separately from other drugs and protected from environmental extremes until used in 
the trial. Tepotinib should be stored at or below 25°C. Any deviations from the recommended 
storage conditions should be immediately reported to the Sponsor, and the IMP should not be used 
until authorization has been received from the Sponsor. The preparation, handling and storage of 
the IMP will be documented.
The IMPs must not be used for any purpose other than the trial in question.
It must be ensured at the trial site that the IMPs are not used after the use-by date. This is to be 
closely monitored by the responsible monitor.
6.8
Investigational Medicinal Product Accountability
The Clinical Trial Supply Department of Nuvisan GmbH is responsible for ensuring IMP 
accountability, including reconciliation of drugs and maintenance of records. Drug accountability 
will also be confirmed by the Trial Monitor.
Upon receipt of IMPs, the responsible person will check for accurate delivery and acknowledge 
receipt by signing or initialing and dating the appropriate documentation and returning it to the 
location specified. A copy will be archived for the Investigator Site File
IMP dispensing will be recorded on the appropriate drug accountability forms so that accurate 
records will be available for verification at each monitoring visit.
Trial site IMP accountability records will include the following:
-
Confirmation of IMP receipt, in good condition and in the defined temperature range
-
The inventory of IMPs provided for the clinical trial and prepared at the site
-
The use of each dose by each subject
-
The disposition (including return, if applicable) of any unused IMP
-
Dates, quantities, batch numbers, vial numbers, expiry dates, formulation (for IMP prepared 
at the site), and the individual subject trial numbers.
The Investigator site should maintain records, which adequately document that subjects were 
provided the doses specified in this protocol, and all IMPs provided were fully reconciled.
Unused IMP must not be discarded or used for any purpose other than the present trial. No IMP 
that is dispensed to a subject may be redispensed to a different subject.
A Trial Monitor will periodically collect the IMP accountability forms. 
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At the conclusion or termination of this trial, all used and unused IMP kits will be destroyed at the 
trial site according to local regulations and institutional guidelines. All used and unused 
medications will be carefully recorded and documented before destruction.
6.9
Assessment of Investigational Medicinal Product Compliance
During the treatment periods, drug administrations will be performed by a Nuvisan GmbH staff 
member in accordance with the specifications of the Investigator. This includes checking the oral 
and buccal cavity with the aid of a flashlight and tongue depressor. The proper administration of 
the trial medication will be documented on the individual eCRF.
6.10
Blinding
This is an open-label study by design. Therefore, blinding is not applicable. (Note: the bioanalytics 
will be performed without knowledge of treatment information. Access to treatment information 
will be restricted and defined in a Data Access Plan).
6.11
Emergency Unblinding
Not applicable. 
6.12
Treatment of Overdose
An overdose is defined as any dose greater than the highest daily dose included in a clinical trial 
protocol or planned for an individual subject enrolled in the trial. Even if it does not meet other 
criteria for an SAE, any overdose must be recorded in the trial medication section of the eCRF and 
reported to Drug Safety in an expedited manner using the SAE Report Form, and following the 
procedure in Section 7.4.
The effects of an overdose of tepotinib are unknown, and therefore no standard treatment is 
currently established. In the event of an overdose, the Investigator or treating physician should use 
appropriate clinical judgment for the management of any clinical symptoms or evaluation results.
6.13
Medical Care of Subjects after End of Trial
Not applicable in a trial with healthy subjects.
7
Trial Procedures and Assessments 
7.1
Schedule of Assessments
Study procedures are the same for both periods. A detailed schedule of trial 
procedures/assessments is provided in Table 1.
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Prior to performing any trial assessments that are not part of routine medical care for the subject, 
the Investigator will obtain written informed consent as described in Section 9.2.
7.1.1
Screening Examination
All subjects will undergo an entry examination to evaluate their health status and their eligibility 
for inclusion in the study. The Screening examination will be conducted not more than 21 days 
prior to the planned first drug administration, ie between Day -21 to Day -2 before commencing 
to first study period. Only subjects who meet the inclusion criteria and none of the exclusion 
criteria will be admitted to the trial. 
Prior to Screening examination, the subjects will receive a screening number for identification. 
Eligible subjects will receive a random number upon enrolment into the study. 
There is a notification on the subject’s card as well as in the electronic subjects’ data base on the 
last participation in a trial. In addition, all subjects are reported to a central checking organization 
(VIP Check) before inclusion into the trial.
Prior to any Screening examinations the subjects must sign the Informed Consent Form (ICF). 
At Screening (Days -21 to -2), the following assessments will be performed (Table 1):

Recording of demographic information including body height, body weight and BMI

Recording of medical history

Physical examination

Measurement of vital signs

12-lead safety ECG recording

Blood and urine sampling for safety laboratory assessments

Serological tests for hepatitis B, C, and HIV1/HIV2 and coagulation tests

Serum Pregnancy test (for females)

Urine drug screen (including test for cotinine)

Alcohol breath test

Assessments of AEs

Documentation of prior and concomitant medication

Preliminary evaluation of inclusion and exclusion criteria.
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7.1.2
Treatment Periods
The subjects willing to participate in the trial will only be included when all Screening examination 
procedures have demonstrated that all inclusion criteria and none of the exclusion criteria apply. 
Subjects will be assigned to a random number within the trial prior to the first administration. 
For time points and assessments please refer to Table 1.
Day -1 (Admission)
Subjects will be admitted to the clinic in the morning of Day -1 until completion of the 72 h 
assessments in the morning of Day 4 of each period.
In each period, the following assessments will be performed:

Physical examination

Measurement of vital signs 

12-lead safety ECG recording (as triplicate)

Blood and urine sampling for safety laboratory assessments 

Pregnancy test (in urine)

Urine drug screen (including test for cotinine) 

Alcohol breath test

Assessment of AEs

Documentation of concomitant medication

Evaluation of inclusion and exclusion criteria (Period 1 only)

Blood sampling for PGx (Period 1 only).
Days 1 to 4 (inpatient)
Prior to dosing on Day 1 the following assessments will be done:

Measurement of vital signs 

12-lead safety ECG recording

Blood and urine sampling for safety laboratory assessments 

Pre-dose PK blood sample for determination of tepotinib and its metabolites. 
After completion of pre-dose assessments study drug will be administered in the morning of Day 1 
of each period as the following: 
Study drug will be administered in both periods in the fasted state together with 200 mL of water.
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A detailed guidance on dosage and administration is provided in Section 6.2.
After dosing the following assessments will be performed at the time points given in the Schedule 
of Assessments (Table 1):

PK blood samples for determination of tepotinib and its metabolites will be taken regularly 
until 72 h (Day 4) post-dose before discharge (for time points please refer to Table 1)

Measurement of vital signs and 12-lead safety ECG recordings on Day 1 (2 h and 8 h post-
dose), Day 2 and Day 4 before discharge

Blood and urine sampling for safety laboratory assessments on Day 2 and Day 4 before 
discharge

Physical examination (only on Day 2 and Day 4 before discharge)

Regular assessment of AEs and concomitant medication.
After completion of the Day 4 assessments (72 h measurements) subjects will be discharged.
Days 5 to 8 (ambulatory)
Subjects will return to the clinic for daily blood sampling to determine the PK of tepotinib and its 
metabolites. Additionally, AEs will be monitored and concomitant medications will be recorded.
The washout period will be at least 21 days between Day 1 of each period (see Figure 2).
Restrictions:
A detailed listing of restrictions during the trial is provided in Section 6.5.
7.1.3
End of Trial Visit
The End of Trial examination has to verify that all values tested in the Screening have remained 
within a clinically acceptable range. The assessments will be performed 21 days (± 1 day) after 
tepotinib administration in the second period. Unacceptable values and AEs will be followed up 
until they return to the reference ranges/resolved or there is an adequate explanation which is not 
related to the trial.
The following assessments will be performed:

Physical examination

Measurement of vital signs 

12-lead ECG recording

Blood and urine sampling for safety laboratory assessments 

Serum Pregnancy test (for females)
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
Assessment of AEs

Documentation of concomitant medication.
No medical treatment is planned after the End of Trial.
The End of Trial is defined as the last contact (related to this trial) of the last subject undergoing 
the trial.
7.2
Demographic and Other Baseline Characteristics
At Screening, the following demographic data will be collected: date of birth, sex (gender), race, 
ethnicity, height, weight, and BMI.
Furthermore, the following will be documented:
Clinically relevant findings in the medical history are recorded
Prior medication within 14 days of Screening and concomitant medication at Screening (any 
prescribed medicine or over-the-counter drug or dietary supplement including herbal remedies, 
vitamins, and minerals)
Smoking status, alcohol intake
Female status (postmenopausal, sterilization).
7.3
Efficacy Assessments
Not applicable.
7.4
Assessment of Safety
The safety profile of the IMP will be assessed through the recording, reporting and analysis of 
baseline medical conditions, AEs, physical examination findings including vital signs and 
laboratory tests.
Comprehensive assessment of any apparent toxicity experienced by each subject will be performed 
from the time of giving informed consent and throughout the trial. The investigator will report any 
AEs, whether observed by the Investigator or reported by the subject (see Section 7.4.1.2). The 
reporting period for AEs is described in Section 7.4.1.3.
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7.4.1
Adverse Events
7.4.1.1
Adverse Event Definitions
Adverse Event
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product, regardless of causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product. 
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.
The Investigator is required to grade the severity or toxicity of each AE. Investigators will 
reference the National Cancer Institute (NCI) - Common Terminology Criteria for AEs 
(CTCAE), version 5.0 (publication date: 27 Nov 2017), a descriptive terminology that can be used 
for AE reporting. A general grading (severity/intensity; hereafter referred to as severity) scale is 
provided at the beginning of the above referenced document, and specific event grades are also 
provided. If the severity of a particular AE is not specifically graded by the guidance document, 
the Investigator is to use the general NCI-CTCAE definitions of Grade 1 through Grade 5 
following his or her best medical judgment.
The 5 general grades are:
Grade 1 or Mild
Grade 2 or Moderate
Grade 3 or Severe 
Grade 4 or Life-threatening 
Grade 5 or Death. 
According to Sponsor convention, any clinical AE with severity of Grade 4 or 5 must also be 
reported as an SAE. However, a laboratory abnormality of Grade 4, such as hemoglobin decreased 
or neutrophils count decreased, is considered serious only if the condition meets one of the serious 
criteria described below.
If death occurs, the primary cause of death or event leading to death should be recorded and 
reported as an SAE. “Fatal” will be recorded as the outcome of this specific event and death will 
not be recorded as separate event. Only, if no cause of death can be reported (eg, sudden death, 
unexplained death), the death per se might then be reported as an SAE.
Investigators must also systematically assess the causal relationship of AEs to the IMP (including 
any other non-IMPs, or medical procedures, as applicable, etc.) using the following definitions. 
Decisive factors for the assessment of causal relationship of an AE to the IMP include, but may 
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not be limited to, temporal relationship between the AE and the IMP, known side effects of the 
IMP, medical history, concomitant medication, course of the underlying disease, trial procedures.
Unrelated:
Not 
reasonably 
related 
to 
the 
IMP. 
AE 
could 
not 
medically 
(pharmacologically/clinically) be attributed to the IMP/study treatment under trial in 
this clinical trial protocol. A reasonable alternative explanation must be available
Related:
Reasonably related to the IMP. AE could medically (pharmacologically/clinically) 
be attributed to the IMP/study treatment under trial in this clinical trial protocol. 
Abnormal Laboratory Findings and Other Abnormal Investigational Findings
Abnormal laboratory findings and other abnormal investigational findings (for example, on an 
ECG trace) should not be reported as AEs unless they are associated with clinical signs and 
symptoms, lead to treatment discontinuation or are considered otherwise medically important by 
the Investigator. If a laboratory abnormality fulfills these criteria, the identified medical condition 
(for example, anemia, increased ALT) must be reported as the AE rather than the abnormal value 
itself.
Serious Adverse Events
An SAE is any untoward medical occurrence that at any dose:
Results in death
Is life-threatening (Note: The term “life-threatening” refers to an event in which the subject is 
at risk of death at the time of the event, not an event that hypothetically might have caused death 
if it was more severe.)
Requires inpatient hospitalization or prolongs an existing hospitalization
Results in persistent or significant disability or incapacity
Is a congenital anomaly or birth defect
Is otherwise considered to be medically important. (Note: Important medical events that may 
not result in death, be life-threatening, or require hospitalization may be considered as SAEs 
when, based upon appropriate medical judgment, they may jeopardize the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above. Examples 
of such events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse.)
For the purposes of reporting, any suspected transmission of an infectious agent via an IMP is also 
considered an SAE, as described in Section 7.4.1.4
Events that Do Not Meet the Definition of an SAE
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Elective hospitalizations to administer, or to simplify trial treatment or trial procedures (for 
example, an overnight stay to facilitate chemotherapy and related hydration therapy application) 
are not considered SAEs. However, all events leading to unplanned hospitalizations or unplanned 
prolongation of an elective hospitalization (for example, undesirable effects of any administered 
treatment) must be documented and reported as SAEs.
Events Not to Be Considered as AEs/SAEs
Medical conditions present at the initial study visit that do not worsen in severity or frequency 
during the study are defined as Baseline Medical Conditions, and are not to be considered AEs.
7.4.1.2
Methods of Recording and Assessing Adverse Events
At each trial visit, the subject will be queried on changes in his or her condition. During the 
reporting period, any unfavorable changes in the subject’s condition will be recorded as AEs, 
whether reported by the subject or observed by the investigator. 
Complete, accurate and consistent data on all AEs experienced for the duration of the reporting 
period (defined below) will be reported on an ongoing basis in the appropriate section of the eCRF. 
All SAEs and all non-serious AEs of special interest must be additionally documented and reported 
using the appropriate Report Form as described in Section 7.4.1.4.
It is important that each AE report include a description of the event, its duration (onset and 
resolution dates and times when it is important to assess the time of AE onset relative to the 
recorded treatment administration time), its severity, its causal relationship with the trial treatment, 
any other potential causal factors, any treatment given or other action taken, including dose 
modification or discontinuation of the IMP, and its outcome. In addition, serious cases should be 
identified and the appropriate seriousness criteria documented.
Specific guidance can be found in the eCRF Completion and Monitoring Conventions.
7.4.1.3
Definition of the Adverse Event Reporting Period
The AE reporting period for safety surveillance begins when the subject is initially included in the 
trial (date of first signature of informed consent) and continues until the End of Trial Visit. 
Any SAE assessed as related to the IMP must be reported whenever it occurs, irrespective of the 
time elapsed since the last administration of the IMP. 
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7.4.1.4
Procedure for Reporting Serious Adverse Events, Adverse 
Events of Special Interest
Serious Adverse Events
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (within a maximum of 24 h after becoming aware of the event) inform the Sponsor 
or its designee in writing. All written reports should be transmitted using the SAE Report Form, 
which must be completed by the Investigator following specific completion instructions.
In exceptional circumstances, an SAE (or follow-up information) may be reported by telephone; 
in these cases, a written report must be sent immediately thereafter by fax or e-mail. Names, 
addresses, and telephone and fax numbers for SAE reporting will be included in the trial-specific 
SAE Report Form. 
Relevant pages from the eCRF may be provided in parallel (for example, medical history, 
concomitant drugs). Additional documents may be provided by the Investigator, if available (for 
example, laboratory results, hospital report, autopsy report). In all cases, the information provided 
on the SAE Report Form must be consistent with the data about the event recorded in the eCRF.
The Investigator must respond to any request for follow-up information (for example, additional 
information, outcome, final evaluation, other records where needed) or to any question the 
Sponsor/designee may have on the AE within the same timelines as those noted above for initial 
reports. This is necessary to ensure prompt assessment of the event by the Sponsor or designee and 
(as applicable) to allow the Sponsor to meet strict regulatory timelines associated with expedited 
safety reporting obligations.
Requests for follow-up will usually be made via the responsible Monitor, although in exceptional 
circumstances the Global Drug Safety department may contact the Investigator directly to obtain 
further information or to discuss the event.
Adverse Events of Special Interest
Healthy subjects might experience asymptomatic elevations in serum lipase and amylase. Any 
elevation in serum lipase and amylase of Grade ≥3 will lead to the recording of an AE of special 
interest (AESI). The severity of these AEs should be defined based on clinical judgment of the 
Investigator and defined according to NCI-CTCAE Severity Scale. 
In the event of a non-serious AESI, the Investigator will complete the AESI Report Form and send 
it to the sponsor/designee within 24 h after becoming aware of the event. Serious AESIs must be 
reported in an expedited manner as SAEs as outlined above.
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7.4.1.5
Safety Reporting to Health Authorities, Independent Ethics 
Committees/ Institutional Review Boards and Investigators
The Sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations.
The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (particularly deaths) involving trial subjects to the IEC that approved the trial.
In accordance with ICH GCP [7], the Sponsor/designee will inform the Investigator of “findings 
that could adversely affect the safety of subjects, impact the conduct of the trial or alter the IEC’s 
approval/favorable opinion to continue the trial. In particular and in line with respective 
regulations, the Sponsor/designee will inform the Investigator of AEs that are both serious and 
unexpected and are considered to be related to the administered product (“suspected unexpected 
serious adverse reactions” [SUSARs]). The Investigator should place copies of Safety Reports in 
the Investigator Site File. National regulations with regard to Safety Report notifications to 
Investigators will be taken into account.
When specifically required by regulations and guidelines, the Sponsor/designee will provide 
appropriate Safety Reports directly to the concerned lead IEC and will maintain records of these 
notifications. When direct reporting is not clearly defined by national or site-specific regulations, 
the Investigator will be responsible for promptly notifying the concerned IEC of any Safety 
Reports provided by the Sponsor/designee and of filing copies of all related correspondence in the 
Investigator Site File.
For trials covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities regarding 
the reporting of SAEs/SUSARs/Safety Issues will be carried out in accordance with that Directive 
and with the related Detailed Guidance documents.
7.4.1.6
Monitoring of Subjects with Adverse Events
AEs are recorded and assessed continuously throughout the trial (see Section 7.4.1.3) and are 
assessed for final outcome at the End of Trial Visit. All SAEs ongoing at the End of Trial Visit 
must be monitored and followed up by the Investigator until stabilization or until the outcome is 
known, unless the subject is documented as “lost to follow-up”. Reasonable attempts to obtain this 
information must be made and documented. It is also the responsibility of the Investigator to ensure 
that any necessary additional therapeutic measures and follow-up procedures are performed. 
7.4.2
Pregnancy and In Utero Drug Exposure 
Only pregnancies considered by the Investigator to be related to trial treatment (for example, 
resulting from a drug interaction with a contraceptive medication) are considered to be AEs. This 
study does not allow inclusion of females of child-bearing potential under hormonal contraception.
However, all pregnancies with an estimated conception date during the period defined in Section
7.4.1.3 must be recorded by convention in the AE page/section of the eCRF. The same rule applies 
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to pregnancies in female partners of male subjects. The Investigator must notify the 
Sponsor/designee in an expedited manner of any pregnancy using the Pregnancy Report Form, 
which must be transmitted according to the same process as described for SAE reporting in Section 
7.4.1.4. 
Investigators must actively follow up, document and report on the outcome of all these 
pregnancies, even if the subjects are withdrawn from the trial.
The Investigator must notify the Sponsor/designee of these outcomes using the Pregnancy Report 
Form. If an abnormal outcome occurs, the SAE Report Form will be used if the subject sustains 
an event and the Parent-Child/Fetus Adverse Event Report Form if the child/fetus sustains an 
event.
Any abnormal outcome must be reported in an expedited manner as described in Section 7.4.1.4, 
while normal outcomes must be reported within 45 days after delivery.
In the event of a pregnancy in a subject occurring during the course of the trial, the subject must 
be discontinued from trial medication immediately. The Sponsor/designee must be notified 
without delay and the subject must be followed as mentioned above.
7.4.3
Clinical Laboratory Assessments
Fasted blood and urine samples will be collected for the clinical laboratory tests (hematology, 
biochemistry, coagulation, virology, drugs of abuse, hormones, and urinalysis) following the 
timing noted in the Schedule of Assessments (Table 1). Additional laboratory safety examinations 
during the course of the trial are at the discretion of the Investigator. 
All blood and urine samples must be clearly identified and will be worked up and analyzed in 
Nuvisan's clinical laboratory. Any abnormalities in any of the laboratory parameters will be judged 
by a physician individually in relation to the reference ranges from the laboratory.
The Sponsor should receive a list of laboratory normal ranges before shipment of the IMP. Any 
change in laboratory normal ranges during the trial should be forwarded to the Sponsor, including 
laboratory certificates.
All safety laboratory examinations will be carried out under fasting conditions. Some additional 
parameters may be routinely analyzed by the laboratory after abnormal findings, or requested by 
the Investigator, including but not limited to eg microscopic differential blood count, direct 
bilirubin and creatine phosphokinase myocardium/brain type.
In case of positive findings of blood, protein, nitrite or leucocytes in the urinalysis, a subsidiary 
microscopic examination of the sediment will be performed.
For all findings with major deviation and/or possible pathological relevance, follow-up 
examinations will be carried out until the deviation returns to normal or the absence of pathological 
relevance can be confirmed. If a deviation considered clinically relevant has not returned to a 
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normal or not clinically relevant value when it is checked during the screening laboratory tests, the 
subject will not be included in the trial. Laboratory abnormalities considered clinically relevant by 
the Investigator will be reported as AE. 
Pregnancy testing (serum or highly sensitive urine, as required by local regulations) will be 
conducted at Screening, on Day -1 and at the end of relevant systemic exposure of the study 
intervention to confirm non-pregnant status of female participants as per Inclusion Criteria
(Section 5.3.1) the study.
The following parameters will be determined as summarized in Table 2.
The amount of blood sampled in this trial is specified in Appendix II.
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Table 2
Clinical Laboratory Evaluations
Biochemistry
Aspartate aminotransferase
Alanine aminotransferase
Alkaline phosphatase
γ-Glutamyl-transferase
Lactate dehydrogenase
Creatine phosphokinase b
Amylase
Lipase
Bilirubin (total) a
Cholesterol
Triglycerides
Uric acid
Sodium
Potassium
Creatinine
Urea
Glucose
Cystatin C (if applicable)
Hematology 
Hematocrit
Hemoglobin
Red blood cell count
Mean corpuscular volume
Mean corpuscular hemoglobin
Mean corpuscular hemoglobin 
concentration
Platelet count 
White blood cell 
count
White blood cell differentials and 
absolute counts c:
Basophils
Eosinophils
Lymphocytes
Monocytes
Neutrophils 
Coagulation
Prothrombin Time (PT) 
International Normalized Ratio (INR)
Activated partial thromboplastin time (aPTT)
Urinalysis 
pH
Nitrite
Protein 
Glucose
Ketone bodies
Urobilinogen 
Bilirubin
Urine pregnancy 
test, females only
Leucocytes
Blood
Microscopic examination d
Urine drug screen
Cocaine
Amphetamines
Methamphetamines
Opiates
Barbiturates
Benzodiazepine
Methadone
Cannabinoids
Tricyclic antidepressants
Cotinine
Ecstasy
Other tests
Hepatitis B surface antigen
Hepatitis C antibody
HIV1/HIV2 antibodies
Follicle stimulating hormone (if applicable, females only to confirm post-menopausal status)
Thyroid stimulating hormone
Serum beta-HCG pregnancy test (females only)
eGFR e
Alcohol breath test
eGFR = estimated glomerular filtration rate, HIV = human immunodeficiency virus, beta-HCG = beta-human chorionic 
gonadotropine
a
In case of an increased bilirubin (total) the direct bilirubin will be determined. 
b
In case of an increased creatine phosphokinase (CK), myocardium/brain type (CK-MB) will be determined; if 
the ratio of CK/CK-MB is above 6, troponin will be determined as well.
c
In case of abnormal findings, manual differential blood count can be requested by the Investigator.
d
Only if blood, protein, nitrite, or leukocytes are positive on the dipstick.
e
Estimated glomerular filtration rate calculated using the Cockcroft-Gault equation.
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7.4.4
Vital Signs, Physical Examinations, and Other Assessments
7.4.4.1
Vital Signs
Blood pressure (systolic blood pressure [mmHg] and diastolic blood pressure [mmHg]) will be 
measured per the oscillometric method using an automated device, which also indicates the 
corresponding pulse rate. Blood pressure and pulse rate will be measured after at least 5 min in a 
supine position, according to the Schedule of Assessments (see Table 1).
Body temperature will be measured auricular.
Further vital sign measurements during the trial are at the discretion of the Investigator.
7.4.4.2
Physical Examination
A standard examination will be performed including general appearance, skin, head, neck 
(including thyroid), eyes, ears, nose, throat, abdomen, as well as neurological, peripheral vascular, 
musculoskeletal, cardiovascular and pulmonary system. 
Physical examination will be scheduled according to the Schedule of Assessments (see Table 1). 
Further physical examinations during the trial are at the discretion of the Investigator. Any relevant 
findings are to be recorded on the Medical History form in the eCRF (for findings from the past 
that occurred prior to ICF signature) or on the AE form in the eCRF (for findings presently 
occurring; events existing but unresolved prior to drug administration).
7.4.4.3
Electrocardiogram 
12-lead ECGs will be recorded according to the Schedule of Assessments (see Table 1) using the 
ECG system Cardio Perfect®, Welch Allyn. The ECGs will be recorded in a supine position after 
at least 5 min rest. 
Per time-point, the ECG will be stored electronically, printed and reviewed in a timely manner by 
the Investigator. The original printout will be stored with the subject’s source data. Electronic data 
may be transferred to a central ECG laboratory for central reading and further analysis; these 
results would be reported separately.
ECG printouts will be signed and dated electronically by the person evaluating the ECG. The ECG 
will be interpreted by the Investigator (normal/abnormal). For abnormal ECGs, the clinical 
significance (yes/no) must be judged by the Investigator and the abnormality is to be specified.
Additional ECGs during the trial are at the discretion of the Investigator.
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7.4.4.4
Alcohol Breath Test
A commercially available breath analyzer (Alcotest 6510, Draeger Safety GmbH) will be used to 
determine the concentration of alcohol in the subject’s breath according to the Schedule of 
Assessments (see Table 1). 
Additional alcohol breath tests during the trial are at the discretion of the Investigator.
7.5
Pharmacokinetics
7.5.1
Blood Sampling
On the PK profiling day, an indwelling venous catheter will be positioned in a suitable forearm 
vein for blood sampling and should be kept, if possible, until at least 24 h after dosing. After 
removing the indwelling venous cannula, samples will be taken by venipuncture.
At visits where assessment time points coincide with each other, the vital signs and ECG 
assessments should be performed slightly before the specific time point and the PK blood sampling 
should be performed on time.
Plasma concentrations of tepotinib and its metabolites MSC2571109A and MSC2571107A will 
be determined in each period according to the sampling schedule outlined in the Schedule of 
Assessments (see Table 1). The exact date and time of sample collection must be recorded in the 
eCRF and will be used in the calculation of PK parameters. Blood samples should be taken as 
close as possible to the scheduled time points. Samples taken outside of the time periods shown in 
Table 3 need an explanation and will be considered as protocol violation.
Table 3
Time Windows
Planned Blood Sampling
Time Windows (min)
Pre-dose
- 60
0.25 - 1 h post-dose
± 2
> 1 h - 12 h post-dose
± 5
> 12 h - 48 h post-dose
± 15
> 48 h - 168 h post-dose
± 30
Concentrations of tepotinib and its metabolites MSC2571109A and MSC2571107A will be 
measured using a validated liquid chromatography-tandem mass spectrometry method at Nuvisan. 
The assays will be carried out in accordance with the applicable Good Clinical Practice and Good 
Laboratory Practice regulations and the EMA reflection paper. A separate bioanalytical protocol 
will be provided before the start of the analytical part of the trial. Full details of the bioanalytical 
method used will be described in a separate bioanalytical report.
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7.5.2
Calculation of Pharmacokinetic Variables
Noncompartmental computation of PK parameters will be performed using the software Phoenix® 
WinNonlin® 6.4 or higher (Certara, L.P., Princeton, New Jersey). For definitions of PK 
parameters, see Table 4.
Table 4
Definition of PK Parameters for Tepotinib and its Metabolites After 
Single Dose Administration
Symbol
Definition
AUC0-t
Area under the plasma concentration-time curve (AUC) from time zero (= dosing time) to 
the last sampling time (tlast) at which the concentration is at or above the lower limit of 
quantification (LLOQ), calculated per the mixed log linear trapezoidal rule (ie linear up/log 
down)
AUC0-∞
Area under the plasma concentration-time curve from time zero (= dosing time) 
extrapolated to infinity, calculated as AUC0-t + AUCextra. AUCextra represents the 
extrapolated part of AUC0-∞ calculated by Clastpred/λz, where Clastpred is the predicted plasma 
concentration at the last sampling time point, calculated from the log-linear regression line 
for λz determination at which the measured plasma concentration is at or above LLOQ
Cmax
Maximum plasma concentration observed
tlast
The last sampling time at which the concentration is at or above the lower limit of 
quantification
tmax
Time to reach the maximum plasma concentration
t1/2
Terminal half-life, calculated as ln2/λz
λz
Terminal rate constant determined from the terminal slope of the log-transformed plasma 
concentration curve using linear regression on terminal data points of the curve
CL/f 
Apparent total body clearance of drug from plasma following oral/extravascular 
administration, calculated as dose/AUC0-∞, only parent drug, will not be calculated for the 
metabolites
Vz/f 
Apparent volume of distribution during the terminal phase following oral/extravascular 
administration, will not be calculated for the metabolites
AUCextra
The AUC from time tlast extrapolated to infinity
AUCextra%
AUCextra% = (AUCextra / AUC0-∞) x 100
Individual PK parameters will be calculated using actual sampling times. The pre-dose sample will 
be considered as if it had been taken simultaneously with the administration of study drug. PK 
variables will be evaluated and listed for all subjects who provide sufficient concentration-time 
data.
Concentrations below the lower limit of quantification (< LLOQ), which are before the last 
quantifiable data point, will be taken as zero for calculating the AUC.
7.6
Biomarkers
Biomarkers are not determined in this trial.
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7.7
Pharmacogenetics
Pharmacogenetic sampling is mandatory for trial participation. An additional separate ICF will be 
used. One blood sample should be collected in duplicate on Day -1 of the first treatment period 
prior to administration. The pharmacogenetic samples will be analyzed conditionally in case of 
unexpected PK profiles. The results of the PGx analysis, as applicable, will be described in a 
separate report.
Storage and analyses of samples will be handled according to the specifications described in the 
ICF.
7.8
Other Assessments
Not applicable.
8
Statistics
8.1
Statistical Hypotheses
The following null hypothesis for the ratio of the geometric means (GeoMean) will be used to 
assess bioequivalence
H0:
µT/µR ≤
or 1.2500 ≤µT/µR for at least one parameter (AUC0-t
or 
AUC0-∞or Cmax)
H1:
00 < µT/µR < 1.2500 for all parameters (AUC0-t and AUC0-∞and Cmax)
where µT and µR are the geometric means for the test and reference treatment respectively.
The test treatment is 5 tablets of the 100 mg dose strength of TF3 and reference treatment is 
2 tablets of the 250 mg dose strength of TF3, both under fasting condition. 
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8.2
Sample Size
The total and mixed intrasubject variability CVs (%) observed in study MS200095-0044 for
AUC0-t and Cmax of tepotinib are summarized in Table 5 (total and mixed intra-individual CV for 
AUC0-∞was very similar to that of AUC0-t and is not listed separately).
Table 5
Overview of the PK-Variability Observed in Tepotinib Study 
MS200095-0044
Study Part
Formulation
(Condition)
Arm
AUC0-t
Cmax
Total 
Geometric 
CV%
Mixed intra-
individual 
CV%
Total 
Geometric 
CV%
Mixed intra-
individual 
CV%
Part A
TF3 vs TF2 (fasted)
TF3 (fasted)
21.0
22.5
TF2 (fasted)
23.4
15.77
20.6
13.94
Part B
TF2 (fed versus fasted) 
TF2 (fed)
25.1
19.6
TF2 (fasted)
38.1
17.96
29.5
12.67
Part C
TF3 (fed versus fasted)
TF3 (fed)
25.0
17.0
TF3 (fasted)
19.8
14.93
15.3
16.79
AUC0-t = area under the plasma concentration-time curve from time zero to the last sampling time at which the 
concentration is at or above the lower limit of quantification, TF2/3 = tablet formulation 2/3; Cmax = maximum plasma 
concentration, CV = coefficient of variation.
Overall, the total variability in AUC and Cmax was between 15.3% and 25.0% for TF3. The mixed 
intrasubject variabilities of AUC and Cmax ranged between 12.67% and 17.96% across all 
investigated combinations of formulation and condition. 
Assuming that the within-subject variability for the comparison between the test and reference 
treatment will be similar to that of Part A in MS200095-0044 (i.e., CV% = 15.77), and with an 
assumed geometric mean ratio Test/Reference (GMR T/R) of 0.95, a one-sided alpha level of 0.05, 
16 evaluable subjects will be needed to provide approximatively 90% power to show 
bioequivalence. A drop-out compensation of 2 subjects will be added. In total, 18 subjects will be 
randomized. If the actual CV is up to 18.4%, the sample size of 16 evaluable subjects would still 
result in approximately 80% power to show bioequivalence.
8.3
Randomization
Refer to Section 6.3 for the technical and logistical aspects of treatment allocation. 
A total of 18 subjects will be randomized. Subjects will be randomized to 1 of 2 sequences at a 
ratio of 1:1:
Sequence 1: 5 x 100 mg (Test) – 2 x 250mg (Reference)
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Sequence 2: 2 x 250 mg (Reference) – 5 x 100 mg (Test)
A computer-generated randomization scheme will be provided by Nuvisan GmbH CTS 
Department. 
8.4
Endpoints
8.4.1
Primary Endpoints
AUC0-t, AUC0-∞and Cmax of tepotinib calculated from concentration data obtained from time 
zero to 168 h post-dose of each period
8.4.2
Secondary Endpoints
tmax, t1/2, apparent total body clearance considering the fraction of dose absorbed (CL/f), and 
apparent volume of distribution during terminal phase (Vz/f) of tepotinib observed from time 
zero to 168 h post-dose of each period
Occurrence of TEAEs (incidence, frequency, intensity and causality), occurrence of changes in 
safety laboratory assessments, 12-lead ECGs and vital signs.
8.4.3
Exploratory Endpoints
PK profiles of tepotinib metabolites: 
AUC0-t, AUC0-∞, Cmax, tmax, t1/2 of tepotinib metabolites observed from time zero to 168 h post-
dose of each period
Genetic variants and mutations in genes that potentially influence PK of tepotinib.
8.5
Analysis Sets
8.5.1
Safety Analysis Set
The Safety analysis set will be defined for each part and will include all subjects who have received 
at least 1 dose of planned IMP and have had 1 subsequent safety assessment. 
8.5.2
Definition of Pharmacokinetic Analysis Set 
The PK Analysis Set will include all subjects without any relevant protocol deviations with respect 
to PK and absence of factors likely to affect the comparability of PK results, with adequate trial 
medication compliance, and who have valid primary endpoints for both treatments. 
All PK analyses will be based on this analysis set.
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8.6
Description of Statistical Analyses
8.6.1
General Considerations
Statistical analyses will be performed using the computer program package SAS® System for 
Windows™ (Version 9.4 or later; SAS Institute, Cary, North Carolina, USA).
The results of this trial will be reported using summary tables, figures, and data listings, as 
appropriate. All data will be summarized by treatment and/or scheduled time point, as appropriate.
For demographic, baseline and safety assessments, continuous measurements will be summarized 
by means of descriptive statistics (ie number and percentage of observations, number and 
percentage of missing observations, mean, standard deviation [SD], median, 25th and 75th
percentiles, minimum, and maximum) and categorical data will be summarized by means of 
frequency tables (ie count and percentages), if not stated otherwise.
Concentrations of tepotinib and its metabolites in plasma will be presented in tables and 
descriptively summarized by treatment and nominal time point using n, arithmetic mean, SD, 
standard error of the mean, median, minimum, maximum, and CV%. Values below the LLOQ will 
be taken as zero for descriptive statistics of PK concentrations. Descriptive statistics of PK 
parameters will additionally show the GeoMean, the geometric coefficient of variation (GeoCV%), 
and the 95% CI for the GeoMean.
Graphical displays will be given, where appropriate. PK variables will be evaluated and listed for 
all subjects who provide sufficient concentration-time data. Invalid data will be flagged 
accordingly. 
Missing values will be handled as such and not be replaced by estimates.
Details of the statistical analysis will be described in the statistical analysis plan.
Changes in the conduct of the trial or planned analyses, if any, will be reported in the appropriate 
section of the statistical analysis plan (SAP) and in the clinical trial report.
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8.6.2
Analysis of Primary Endpoints
An analysis of variance (ANOVA) model will be fitted for the log-transformed PK parameters 
Cmax, AUC0-t, AUC0-∞based on the PK analysis set. The model will include treatment, period, 
sequence as fixed effects and subject within sequence as a random effect. 
Treatment differences on the log scale will be estimated for Cmax, AUC0-t, AUC0-∞together with 
their 90% CIs. Point estimates and CIs will be back-transformed to the original scale for the 
comparisons. 
The comparison will be the test treatment (5 x 100 mg TF3) vs the reference treatment (2 x 250 mg 
TF3) under fasting condition. 
The null hypothesis for non-bioequivalence will be rejected if the 90% CI for the ratio of the 
GeoMean lies within the interval 0.8000 to 1.2500 for all primary pharmacokinetic parameters. 
8.6.3
Analysis of Secondary Endpoints
Summary statistics will be provided for all secondary PK parameters in plasma by time point. 
Graphical displays will be given, where appropriate. Details of the statistical analysis will be 
described in the SAP.
8.6.4
Analysis of Safety and Exploratory Endpoints
Safety data analysis will be conducted on the Safety Analysis Set of each part. The number and 
percentage of subjects experiencing at least 1 TEAE will be summarized by treatment as will the 
number of events. Tables by relationship to study drug and by severity will be generated. AEs will 
be coded using Medical Dictionary for Regulatory Activities terminology. All laboratory data will 
be reported with SI units. 
Laboratory parameters will be summarized using descriptive statistics for absolute values and 
change from baseline over time, by post-dose shifts relative to baseline, and data listings of 
laboratory values/out of the normal range. 
Vital signs and ECG data will be summarized by changes from baseline values by treatment using 
descriptive statistics. Clinically significant ECG findings for individual subjects will be listed and 
summarized as appropriate.
PK concentrations will be descriptively summarized. Individual and mean concentration-timeplots 
will be produced in linear and log-linear scale.
Exploratory endpoints will be analyzed with descriptive statistics.
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8.7
Interim and Additional Planned Analyses
Not applicable.
9
Ethical and Regulatory Aspects
9.1
Responsibilities of the Investigator
The Investigator is responsible for the conduct of the trial at the site and will ensure that the trial 
is performed in accordance with this protocol, the ethical principles outlined in the Declaration of 
Helsinki, ICH GCP [7], and any other applicable regulations. The Investigator must ensure that 
only subjects who have given informed consent are included in the trial.
9.2
Subject Information and Informed Consent
An unconditional prerequisite for each subject prior to participation in the trial is written informed 
consent, which must be given before any trial-related activities are carried out. Adequate 
information must therefore be given to the subject by the Investigator or an appropriate designee 
(if local regulations permit) before informed consent is obtained. 
A subject information sheet must be prepared in the local language in accordance with ICH GCP 
[7] and will be provided by the Sponsor for the purpose of obtaining informed consent. In addition 
to providing this written information to a potential subject, the Investigator or a designate will 
inform the subject verbally of all pertinent aspects of the trial, using language chosen so that the 
information can be fully and readily understood by laypersons. The subject will be given sufficient 
time to read the information and the opportunity to ask questions and to request additional 
information and clarification.
After the information is provided by the Investigator, the ICF must be signed and dated by the 
subject and the Investigator. The signed and dated declaration of informed consent will remain at 
the Investigator’s site, and must be safely archived so that the forms can be retrieved at any time 
for monitoring, auditing and inspection purposes. A copy of the signed and dated information and 
ICF should be provided to the subject prior to participation.
Whenever important new information becomes available that may be relevant to informed consent, 
the Investigator will revise the subject information sheet and any other written information to be 
provided to the subjects and submit them to the IEC for review and opinion. Using the approved 
revised subject information sheet and other written information, The Investigator will explain the 
changes to the previous version to each trial subject and obtain new written consent for continued 
participation in the trial. The subject will be given sufficient time to read the information and the 
opportunity to ask questions and to request additional information and clarification about the 
changes.
A separate subject information sheet will be prepared for the PGx testing. The subjects will be 
informed in the written form and verbally about pertinent aspects of the planned PGx testing 
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including an explanation that this additional examination is mandatory for subjects’ participation 
in this clinical trial. Only subjects who have signed and dated the ICF for PGx testing will be 
included in this clinical trial.
9.3
Subject Identification and Privacy
A unique number will be assigned to each subject, immediately after informed consent has been 
obtained. This number will serve as the subject’s identifier in the trial as well as in the clinical trial 
database. All subject data collected in the trial will be stored under the appropriate subject number. 
Only the Investigator will be able to link trial data to an individual subject via an identification list 
kept at the site. For each subject, original medical data will be accessible for the purposes of source 
data verification by the Monitor, audits and regulatory inspections, but patient confidentiality will 
be strictly maintained.
Data protection and privacy regulations will be observed in capturing, forwarding, processing, and 
storing subject data. Subjects will be informed accordingly, and will be requested to give their 
consent on data handling procedures in accordance with national regulations.
9.4
Emergency Medical Support and Subject Card
Subjects will be provided with Emergency Medical Support cards supplied by Nuvisan GmbH for 
use during trial participation in order to provide clinical trial subjects with a way of identifying 
themselves as participating in a clinical trial and to give health care providers access to any 
information about this participation that may be needed to determine the course of medical 
treatment for the subject. The information provided on the Emergency Medical Support card may 
include the process for emergency unblinding (if applicable).
The first point of contact for all emergencies will be the clinical trial Investigator caring for the 
affected subject. The Investigator agrees to provide his or her emergency contact information on 
the card for this purpose. If the Investigator is available when an event occurs, he/she will answer 
any questions. Any subsequent action will follow the standard process established for 
Investigators.
In cases where the Investigator is not available, the Phase 1 facility will provide the appropriate 
means to contact a physician. This includes the provision of a 24-hour contact number at the 
facility, whereby the health care providers will be given access to an appropriate physician to assist 
with the medical emergency.
9.5
Clinical Trial Insurance and Compensation to Subjects
Insurance coverage will be provided for this trial. Insurance conditions will meet good local 
standards, as applicable.
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9.6
Independent Ethics Committee or Institutional Review Board
Prior to commencement of the trial at a given site, this clinical trial protocol will be submitted 
together with its associated documents (including but not limited to Subject Information and ICF, 
insurance certificate, Investigator’s Brochure) to the responsible IEC for its favorable opinion or 
approval, which will be filed in the Investigator Site File. A copy will be filed in the Sponsor Trial 
Master File.
The IEC will be asked to document the date of the meeting at which the favorable opinion or 
approval was given and the members and voting members present. Written evidence of favorable 
opinion or approval that clearly identifies the trial, the clinical trial protocol version and the Subject 
Information and ICF version reviewed should be provided. Where possible, copies of the meeting 
minutes should be obtained.
Amendments to this clinical trial protocol will also be submitted to the concerned IEC, before 
implementation of substantial changes (see Section 10.5). Relevant safety information will be 
submitted to the IEC during the course of the trial in accordance with national regulations and 
requirements.
9.7
Health Authorities
The clinical trial protocol and any applicable documentation (for example, IMP Dossier, Subject 
Information and ICF) will be submitted or notified to the Health Authorities in accordance with 
all local and national regulations for each site.
10
Trial Management
10.1
Case Report Form Handling
Refer to the Manual of Operations for eCRF handling guidelines. 
The main purpose of the eCRF is to obtain data required by the clinical trial protocol in a complete, 
accurate, legible and timely manner. The data in the eCRF should be consistent with the relevant 
source documents.
The Investigator or designee is responsible for ensuring that the data collected in the course of this 
trial is accurate and documented appropriately on all applicable forms. They will then be 
processed, evaluated, and stored in anonymous form in accordance with applicable data protection 
regulations. The Investigator must ensure that the eCRFs and any other associated documents 
forwarded to Sponsor or its designated organization contain no mention of any subject names.
The data will be entered into a validated database. Nuvisan GmbH will be responsible for data 
processing, in accordance with the Sponsor’s data management procedures. Database lock will 
occur once quality control and quality assurance procedures have been completed. PDF files of the 
eCRFs will be provided to the Investigators at the completion of the trial.
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10.2
Source Data and Subject Files
The Investigator must keep a file (medical file, original medical records) on paper or electronically 
for every subject in the trial. It must be possible to identify each subject by using this subject file. 
This file will contain the demographic and medical information for the subject listed below and 
should be as complete as possible. 
Subject’s full name, date of birth, sex, height, weight
Medical history and concomitant diseases
Prior and concomitant therapies (including changes during the trial)
Trial identification, that is, the Sponsor trial number for this clinical trial, and subject number
Dates for entry into the trial (informed consent) and visits to the site
Any medical examinations and clinical findings predefined in this clinical trial protocol
All AEs
Date that the subject left the trial including any reason for early withdrawal from the trial or 
IMP (if applicable).
All documents containing source data must be filed, including, but not limited to ECG recordings, 
and laboratory results. Such documents must bear the subject number and the date of the procedure. 
If possible, this information should be printed by the instrument used to perform the assessment or 
measurement. As necessary, medical evaluation of such records should be performed; all 
evaluations should be documented, signed, and dated by the Investigator.
Electronic subject files will be printed whenever the Monitor performs source data verification. 
Printouts must be signed and dated by the Investigator, countersigned by the Monitor and kept in 
a safe place at the site.
10.3
Investigator Site File and Archiving
Upon initiation of the trial, the Investigator will be provided with an Investigator Site File 
containing all necessary trial documents, which will be completed throughout the trial and updated 
as necessary. The file must be available for review by the Monitor, during Sponsor audits and for 
inspection by Health Authorities during and after the trial, and must be safely archived for at least 
15 years after the end of the trial. The documents to be archived include the Subject Identification 
List and the signed subject ICFs. If archiving of the Investigator Site File is no longer possible at 
the site, the Investigator must notify the Sponsor/designee.
All original subject files (medical records) must be stored at the site (hospital, research institute, 
or practice) for the longest possible time permitted by the applicable regulations, and/or as per ICH 
GCP guidelines [7], whichever is longer. In any case, the Investigator should ensure that no 
destruction of medical records is performed without the written approval of the Sponsor.
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10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities
This trial will be monitored in accordance with the ICH GCP [7] and any other applicable 
regulations. The site Monitor will perform visits to the trial site at regular intervals.
The clinical trial protocol, each step of the data capture procedure, and the handling of the data, 
including the final clinical trial report, will be subject to independent Quality Assurance activities. 
Audits may be conducted at any time during or after the trial to ensure the validity and integrity of 
the trial data. Representatives of the Quality Assurance unit from the Sponsor or a designated 
organization, as well as Health Authorities, must be permitted to access all trial documents and 
other materials at the site, including the Investigator Site File, the completed eCRFs, all IMP and 
IMP accountability records, and the original medical records or files for each subject.
10.5
Changes to the Clinical Trial Protocol
Changes to the clinical trial protocol will be documented in writing. Substantial amendments will 
usually require submission to the Health Authorities and to the relevant IEC for approval or 
favorable opinion. In such cases, the amendment will be implemented only after approval or 
favorable opinion has been obtained.
Minor (non-substantial) protocol amendments, including administrative changes, will be filed by 
the Sponsor and at the site. They will be submitted to the relevant IEC or to Health Authorities 
only where requested by pertinent regulations. Any amendment that could affect the subject’s 
agreement to participate in the trial requires additional informed consent prior to implementation 
following the process as described in Section 9.2.
10.6
Clinical Trial Report and Publication Policy
10.6.1
Clinical Trial Report
After completion of the trial, a clinical trial report will be written by Nuvisan GmbH following the 
guidance in ICH Topic E3 [8].
10.6.2
Publication
The first publication will include the results of the analysis of the primary endpoints. The results 
of this study may be published or presented at scientific meetings. If this is foreseen, the 
Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. This 
allows Merck to protect proprietary information and to provide comments. 
The Sponsor will comply with the requirements for publication of study results.
Posting of data on ClinicalTrials.gov and EudraCT is planned and will occur 12 months after the 
last clinic visit of the final trial subject or another appropriate date to meet applicable requirements.
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11
References Cited in the Text
1. Guidance for Industry; Bioavailability and Bioequivalence Studies submitted for NDAs or 
INDs – General Considerations. FDA CDER Office of Clinical Pharmacology, Mar 2014.
2. Guideline for Industry: Food-Effect Bioavailability Fed Bioequivalence Studies. FDA 
CDER. Dec 2002. 
3. EMA 
GUIDELINE 
ON 
THE 
INVESTIGATION 
OF 
BIOEQUIVALENCE. 
CPMP/EWP/QWP/1401/98 Rev. 1/ Corr ** London, 20 January 2010.
4. Guideline for Bioequivalence Studies for Different Strengths of Oral Solid Dosage Forms, 
PMDA 2012.
5. Guideline for Bioequivalence Studies of Generic Products, PMDA 2012.
6. Recommendations related to contraception and pregnancy testing clinical trials. Clinical 
Trial Facilitation Group (CTFG), Heads of Medicines Agencies. 15 September 2014. 
Downloaded from ‘www.hma.eu’ on 07 November 2017.
7. ICH 
Topic 
E6(R2) 
Guideline 
for 
good 
clinical 
practice 
E6(R2). 
EMA/CHMP/ICH/135/1995. London, 1 December 2016. 1-70.
8. ICH Topic E3. Structure and Content of Clinical Study Reports. CPMP/ICH/137/95, 
London July 1996. 1-47.
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12
Appendices
Appendix I
Signature Pages and Responsible Persons for the Trial
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T e p o t i n i b  (  M S C 2 1 5 6 1 1 9 J )
M S 2 0 0 0 9 5 _ 0 0 3 8
Bi o e q ui v al e n c e of 5 t a bl et s of 1 0 0 m g v s 2 t a bl et s of 2 5 0 m g T F 3 of
t e p oti ni b
Si g n at ur e  P a g e  -  Pr ot o c ol  L e a d
T r i a l  T i t l e :
E u d r a C T  N u m b e r :
A n o p e n-l a b el, si n gl e- d o s e, r a n d o mi z e d, 2- p eri o d, 2-
s e q u e n c e  cr o s s- o v er,  si n gl e- c e nt er  P h a s e  I  tri al  i n
h e alt h y  s u bj e ct s  t o  a s s e s s  t h e  bi o e q ui v al e n c e  of
t e p oti ni b t a bl et f or m ul ati o n 3 a d mi ni st er e d a s 5 t a bl et s
of 1 0 0 m g v ers us 2 t a bl ets of 2 5 0 m g d os e str e n gt h.
2 0 1 9 - 0 0 3 5 7 8 - 1 3
Cli ni c al  Tri al  Pr ot o c ol  D at e  /  0 5- S e p- 2 0 1 9  /  V er si o n  1. 0
V e r si o n :
P r ot o c ol  L e a d:
I a p pr o v e t h e d e si g n of t h e cli ni c al tri al:
Si g n at ur e
N a m e, a c a d e mi c d e gr e e: 
D at e of Si g n at ur e
F u n cti o n  /  Titl e:
I n stit uti o n:
A d d r e s s:
Tel e p h o n e  n u m b er:
E- m ail  a d dr e s s:
M e di c al R e s p o n si bl e / 
M e r c k  H e a l t h c a r e  K  G a A
Fr a nkf urt er Str ass e 2 5 0, 6 4 2 9 3 D ar mst a dt, G er m a ny
D o c u m e nt  N o.  0 9 0 0 b a b e 8 1 2 c d 5 a 9 v  1. 0
O bj e ct  N o.  0 9 0 0 b a b e 8l 2 d 9 4 8 a
C
O
N
F I
D
E
N
T I
A
L
I
N
F
O
R
M
A
T I
O
N
6 0/ 6 5
PI
PI
PI
PI
PI
PI


PI
PI
PI
PI
PI
PI
PI
PI


Te p oti ni b ( M S C 2 1 5 6 1 1 9 J)
Bi oe q ui v ale nce of 5 t a blets of 1 0 0 m g vs 2 t a blets of  25 0 m g T F 3 of 
te p oti ni b
M S 2 0 0 0 9 5 _ 0 0 3 8
C O N F I D E N T I A L
I N F O R M A T I O N
6 2 /6 5
S p o ns or Res p o nsi ble Pers o ns n ot N a me d o n t he C o ver P a ge
Na me:
F u ncti o n / Title:
I nstit uti o n:
Merc k Healt hcare K Ga A
A d dress:
Fra n kf urter Strasse 2 5 0, 6 4 2 9 3 Dar msta dt, Ger ma n y
Tele p h o ne n u m ber:
E- mail a d dress:
Na me:
F u ncti o n / Title:
I nstit uti o n:
Merc k Healt hcare K Ga A 
A d dress:
Fra n kf urter Strasse 2 5 0, 6 4 2 9 3 Dar msta dt, Ger ma n y
Tele p h o ne n u m ber:
E- mail a d dress:
D oc u me nt N o. 0 9 0 0 ba be 8 1 2c d 5a 9 v 1. 0
O bject N o. 0 9 0 0 ba be 8 1 2 d 9 4 8a
Pa ge 6 3 of 6 6
PI
PI
PI
PI
PI
PI


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Appendix II
Blood Volume Sampled in the Clinical Trial
Blood sample for
Amount 
per 
sample 
(mL)
Number of Scheduled Blood Samples per Subject
Total 
amount 
per 
Subject
(mL)
Screening Per Period
No. of 
Periods 
per Part
End of Trial 
Visit
Total
Clinical laboratory tests 
Biochemistry (incl. viral 
serology, TSH and FSH 
levels, if applicable)
4.7
1
4 a
2
1
10
47.0
Hematology
2.7
1
4 a
2
1
10
27.0
Coagulation
3.0
1
3.0
PK
2.0
22 b
2
44
88.0
PGx
2.0
2 c
2
4.0
Total
2
32
2
66
169.0
Note: the number of blood samples may increase above the scheduled number. Blood samples for 
clinical laboratory follow-up determinations may become necessary. Technical failure of PK/PGx blood 
drawing may lead the Investigator to decide immediately to repeat a single blood drawing to have a 
sample. 
Maximal blood volume drawn: Estimate per Subject in this Study 
that will not be exceeded in this planned trial as by experience of the Investigating Institution: 
200
FSH = follicle stimulating hormone, PGx = pharmacogenetics, PK = pharmacokinetics, TSH = thyroid stimulating 
hormone.
Clinical laboratory (biochemistry and hematology) blood samples:
a
Each period: on Day -1, pre-dose on Day 1, on Day 2 and before discharge on Day 4 = 4 samples;
PK blood samples for determination of tepotinib and its metabolites:
b
Each period: pre-dose, 15, 30, 45, 60, 90 min, and 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120, 144 and 
168 h post-dose = 22 samples;
PGx blood samples:
c
PGx blood samples of 2 x 2 mL to be drawn on Day 1 of Period 1 at pre-dose = 2 samples.
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Appendix III
Contraception Guidance
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile, as specified below.
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, consider additional evaluation.
A WOCBP is not:
1. Premenarchal
2. A premenopausal female with 1 of the following:
Documented hysterectomy
Documented bilateral salpingectomy
Documented bilateral oophorectomy
Documentation can come from the site personnel’s review of the female’s medical records, 
medical examination, or medical history interview.
For a female with permanent infertility due to an alternate medical cause other than the 
above, (e.g., mullerian agenesis, androgen insensitivity), investigator discretion applies to 
determine study entry.
3. A postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.

A high follicle-stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in a female not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, more than 1 FSH measurement is required in the 
postmenopausal range.

A female on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if she wishes to 
continue her HRT during the study. Otherwise, she must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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Contraception Guidance:
CONTRACEPTIVES ALLOWED DURING THE STUDY INCLUDE:
Highly Effective Methods That Have Low User Dependency

Implantable progestogen-only hormone contraception associated with inhibition of ovulation

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Vasectomized partner: a highly effective contraceptive method provided that the partner is the sole sexual 
partner of a WOCBP and the absence of sperm has been confirmed. Otherwise, use an additional highly 
effective method of contraception. The spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That Are User DependentCombined (estrogen- and progestogen-containing) hormonal 
contraception associated with inhibition of ovulation

Oral

Intravaginal

Transdermal

Injectable

Progestogen-only hormone contraception associated with inhibition of ovulation

Oral

Injectable

Sexual abstinence: a highly effective method only if defined as refraining from intercourse during the entire 
period of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study.
Notes:
Contraceptive use by men or women is consistent with local regulations on the use of contraceptive methods for 
clinical study subjects.
Highly effective methods are those with a failure rate of <1% per year when used consistently and correctly. 
Typical use failure rates differ from those when used consistently and correctly.
Hormonal contraception may be susceptible to interaction with the study intervention(s), which may reduce the 
efficacy of the contraceptive method. As such, male condoms must be used in addition to hormonal 
contraception. If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable contraceptive methods are limited to those which inhibit ovulation as the primary mode of action.
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception for 
this study. Male condom and female condom cannot be used together (due to risk of failure with friction).
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 66 of 66

SAP_001.pdf: 
Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg 
TF3 of tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
1/1
Appendix 16.1.9
Documentation of Statistical Methods
Integrated Analysis Plan Version 1.0, 22 November 2019
Statistical Analysis Output
WinNonlin Core Output
WinNonlin Plots
Page 1 of 331


Te p oti ni b ( M S C 2 1 5 6 1 1 9 J)
Bi oe q ui v ale nce of  5 ta blets of 1 0 0 m g vs 2 t a blets of  25 0 m g T F 3 of 
te p oti ni b
M S 2 0 0 0 9 5 _ 0 0 3 8  
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C O N F I D E N T I A L
I N F O R M A T I O N
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I nte gr ate d A n al ysis Pl a n
Cli nic al Tri al Pr ot oc ol 
I de ntific ati o n N o.
M S 2 0 0 0 9 5 _ 0 0 3 8
Title
A n o pe n -la bel, si n gle-d ose, ra n d o mize d, 2-peri o d, 2- se q ue nce 
cr oss -o ver, si n gle-ce nter P hase I trial i n healt h y  su bjects t o 
assess t he bi oe q ui vale nce of te p oti ni b ta blet f or m ulati o n 3 
a d mi nistere d as 5 ta blets of 1 0 0 m g vers us 2 ta blets of 2 5 0 m g 
d ose stre n gt h
Tri al P h ase
I
I n vesti g ati o n al Me dici n al 
Pr o d uct(s)
Te p oti ni b ( M S C 2 1 5 6 1 1 9J)
Cli nic al Tri al Pr ot oc ol 
Versi o n
0 5 Se p 2 0 1 9 / Versi o n 1. 0
Inte gr ate d A n al ysis Pl a n 
A ut h or
C o or di n ati n g A ut h or
 M er c k
F u n cti o n
A ut h or / Bi o st ati sti ci a n
 N u vi s a n
I nte gr ate d A n al ysis Pl a n
D ate a n d Versi o n
2 2 N o v 2 0 1 9 / Fi nal Versi o n 1. 0
Inte gr ate d A n al ysis Pl a n 
Re vie wers
F u n cti o n
N a m e
 
 
M e di c al R e s p o n si bl e, M er c k
 
 
, 
, M er c k
 
, M er c k
, M er c k
, M er c k
, M er c k
C o nfi de nti al
T his d oc u me nt is t he pr o pert y of Merc k K Ga A, Dar msta dt, Ger ma n y, or o ne of its affiliate d c o m pa nies.
It is i nte n de d f or restricte d use o nl y a n d ma y n ot - i n f ull or part - be passe d o n, re pr o d uce d, p u blis he d or use d wit h o ut 
e x press per missi o n of Merc k K Ga A, Dar msta dt, Ger ma n y or its affiliate. 
C o p yri g ht © 2 0 1 9 b y Merc k K G a A, D ar mst a dt, Ger m a n y or its aff ili ate. All ri g hts reser ve d.
Pa ge 2 of 3 3 1
PI
PI
PI
PI
PI
PI
PI
PI
PI
PI
PI
PI
PI
PI
PI
PI
PI


Te p oti ni b ( M S C 2 1 5 6 1 1 9 J)
Bi oe q ui v ale nce of  5 ta blets of 1 0 0 m g vs 2 t a blets of  25 0 m g T F 3 of 
te p oti ni b
M S 2 0 0 0 9 5 _ 0 0 3 8  
       Fi n al 1. 0
C O N F I D E N T I A L
I N F O R M A T I O N
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Si g n at ure P a ge
I nte gr ate d A n al ysis Pl a n: M S 2 0 0 0 9 5 _ 0 0 3 8
A n o pe n -la bel, si n gle-d ose, ra n d o mize d, 2 -peri o d, 2 -se q ue nce cr oss-o ver, si n gle -ce nter 
P hase I trial i n healt h y s u bjects t o assess t he bi oe q ui vale nce of te p oti ni b ta blet f or m ulati o n 3 
a d mi nistere d as 5 ta blets of 1 0 0 m g vers us 2 ta blets of 2 5 0 m g d ose stre n gt h 
A p pr o val of t he I A P b y  all Merc k Data A nal ys is Res p o nsi ble s is d oc u me nte d wit hi n Cara . 
Wit h t he a p pr o val wit hi n Cara , t he Merc k res p o nsi ble f or eac h of t he a nal ysis als o ta kes 
res p o nsi bilit y t hat all re vie wers’ c o m me nts are a d dresse d a de q uately.
Merc k res p o nsi ble
D ate
Si g n at ure
, Merc k
Via Cara a p pr o val pr ocess
, 
Via Cara a p pr o val pr ocess
, Merc k
  
Pa ge 3 of 3 3 1
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Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038  
       Final 1.0
C O N F I D E N T I A L
I N F O R M A T I O N
3/25
1
Table of Contents
Integrated Analysis Plan ......................................................................................................1
Signature Page
2
1
Table of Contents..................................................................................3
2
List of Abbreviations and Definition of Terms ....................................5
3
Modification History ............................................................................6
4
Purpose of the Integrated Analysis Plan...............................................6
5
Objectives and Endpoints .....................................................................7
6
Overview of Planned Analyses.............................................................7
6.1
Interim Analysis....................................................................................7
6.2
Final Analysis .......................................................................................8
7
Changes to the Planned Analyses in the Clinical Trial Protocol..........8
8
Protocol Deviations and Analysis Sets.................................................8
8.1
Definition of Protocol Deviations and Analysis Sets ...........................8
8.2
Definition of Analysis Sets...................................................................9
9
General Specifications for Data Analyses ............................................9
10
Trial Subjects......................................................................................11
10.1
Disposition of Subjects and Discontinuations....................................11
10.2
Protocol Deviations ............................................................................12
10.2.1
Important Protocol Deviations............................................................12
10.2.2
Reasons Leading to the Exclusion from an Analysis Set ...................12
11
Demographics and Other Baseline Characteristics.............................12
11.1
Demographics.....................................................................................12
11.2
Medical History ..................................................................................13
11.3
Other Baseline Characteristics............................................................13
12
Previous or Concomitant Medications/Procedures.............................13
13
Treatment Compliance and Exposure.................................................14
14
Efficacy Analyses ...............................................................................14
15
Safety Analyses ..................................................................................14
15.1
Adverse Events ...................................................................................14
15.1.1
All Adverse Events.............................................................................15
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Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038  
       Final 1.0
C O N F I D E N T I A L
I N F O R M A T I O N
4/25
15.1.2
Adverse Events Leading to Treatment Discontinuation.....................16
15.2
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events ...................................................................................16
15.2.1
Deaths .................................................................................................16
15.2.2
Serious Adverse Events......................................................................16
15.2.3
Other Significant Adverse Event........................................................17
15.2.3.1
Adverse Events of Special Interest.....................................................17
15.3
Clinical Laboratory Evaluation...........................................................17
15.4
Vital Signs ..........................................................................................18
15.5
ECG Evaluation..................................................................................18
16
Analyses of Other Endpoints..............................................................19
16.1
Pharmacokinetics................................................................................19
General Specifications for Plasma Concentration Data.....................................................19
General Specifications for PK Parameter Data..................................................................19
16.1.1
Primary Endpoints ..............................................................................20
16.1.2
Secondary Endpoints ..........................................................................21
16.1.3
Exploratory Endpoints........................................................................21
16.1.4
Plasma Concentration Data.................................................................21
16.1.5
Estimation of Individual Pharmacokinetic Parameters.......................22
16.2
Pharmacogenetics ...............................................................................24
17
References...........................................................................................25
18
Appendices .........................................................................................25
Page 5 of 331


Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038  
       Final 1.0
C O N F I D E N T I A L
I N F O R M A T I O N
5/25
2
List of Abbreviations and Definition of Terms
AE
Adverse Event
AESI
ANOVA
Adverse Event of Special Interest
Analysis of VARIANCE
BMI
Body Mass Index
eCRF
Electronic Case Report Form
CSR
Clinical Study Report
CV%
Coefficient of Variation
ECG
Electrocardiogram
GeoCV%
Geometric Coefficient of Variation
GeoMean
Geometric Mean
IAP
Integrated Analysis Plan
ICH
International Conference on Harmonization
IMP
LCI
Investigational Medicinal Product
Lower Confidence Interval Bound
LLOQ
Lower Limit of Quantification
Max
Maximum
MCAR
Missing Completely at Random
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
NCI-CTCAE
National Cancer Institute – Common Terminology Criteria for Adverse 
Events
PD
Pharmacodynamics
PGx
Pharmacogenetics
PK
Pharmacokinetics
PT
Preferred Term
Q1
First Quartile
Q3
Third Quartile
QTcF
Corrected QT interval per Fridericia’s formula
Page 6 of 331


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       Fi n al 1. 0
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S A E
Seri o us A d verse E ve nt
S D T M
S E M
St u d y  Data Ta b ulati o n M o del
Sta n dar d Err or of t he Mea n
S O C
S y ste m Or ga n Class
T E A E
Treat me nt E mer ge nt A d verse E ve nt
T F 3
Ta blet F or m ulati o n 3
U CI
U p per C o nfi de nce I nter val B o u n d
U L O Q
U p per Li mit of Q ua ntificati o n
3
M o dific ati o n Hist or y
U ni q u e
I d e ntifi er f or
V er si o n
D at e of
I A P V er si o n
A ut h or
C h a n g e s fr o m t h e Pr e vi o u s V er si o n
Fi n al 1. 0
2 2 -N O V -2 0 1 9
, 
N u vi s a n
Ori gi n al D o c u m e nt
4
P ur p ose of t he I nte gr ate d A n al ysis Pl a n
T he p ur p ose of t his i nte grate d a nal ys is pla n (I A P) is t o d oc u me nt tec h nical a n d detaile d 
s pecificati o ns f or t he fi nal a nal ysis of data c ollecte d f or pr ot oc ol M S 2 0 0 0 9 5 _ 0 0 3 8 . Res ults of t he 
a nal ys es descri be d i n t his I A P will be i ncl u de d i n t he Cli nical St u d y Re p ort ( C S R). A d diti o nall y, 
t he pla n ne d a nal yses i de ntifie d i n t his I AP will be i ncl u de d i n re g ulat or y su b missi o ns or f ut ure 
ma n uscri pts. A n y  post -h oc or u n pla n ne d a nal ys es perf or me d t o pr o vi de res ults f or i ncl usi o n i n 
t he C S R b ut n ot i de ntifie d i n t his pr os pecti ve I A P will be clearly i de ntifie d i n t he C S R. 
T he I A P is base d u p o n secti o n 8 ( Statistics) of t he trial pr ot oc ol a n d pr ot oc ol a me n d me nts a n d is 
pre pare d i n c o m plia nce wit h I C H E 9. 
Pa ge 7 of 3 3 1
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Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038  
       Final 1.0
C O N F I D E N T I A L
I N F O R M A T I O N
7/25
5
Objectives and Endpoints
Objective
Endpoint
IAP 
section
Primary
Objectives

To demonstrate bioequivalence 
between 5 tablets of the 100 mg dose 
strength of tepotinib tablet formulation 3 
(TF3, test treatment) and 2 tablets of 
the 250 mg dose strength of TF3 
(reference treatment) after single dose 
administration in healthy subjects under 
fasting conditions
Primary Endpoints:

Area under the plasma concentration-
time curve (AUC) from time zero 
(=dosing time) to the last sampling time 
at which the concentration is at or 
above the lower limit of quantification 
(AUC0-t).

AUC from time zero extrapolated to 
infinity (AUC0-∞).

Maximum plasma concentration (Cmax) 
of tepotinib observed from time zero to 
168 h postdose of each period.
16.1.1
Secondary 
Objectives

To further investigate the
Pharmacokinetic (PK) of tepotinib.
Secondary endpoints:

Time to reach Cmax (tmax), terminal 
half-life (t1/2), apparent total body 
clearance considering the fraction of 
dose absorbed (CL/f) and apparent 
volume of distribution during terminal 
phase (Vz/f) of tepotinib observed from 
time zero to 168 h postdose of each 
period.
16.1.2

To further assess the safety and 
tolerability of tepotinib TF3 under 
fasting conditions.

Occurrence of treatment-emergent 
adverse events (TEAEs; incidence, 
frequency, intensity and causality), 
occurrence of changes in safety 
laboratory assessments, 12-lead 
electrocardiograms (ECGs) and vital 
signs.
15
Exploratory
Objectives

To investigate the PK of tepotinib 
metabolites.

To explore the effect of 
pharmacogenetics (PGx) and variations 
of associated genes on the PK profile 
of tepotinib (if applicable).
Exploratory Endpoints:

PK profiles of tepotinib metabolites:
AUC0-t, AUC0-∞, Cmax, tmax, t1/2 of 
tepotinib metabolites observed from 
time zero to 168 h postdose of each 
period.

Genetic variants and mutations in 
genes that potentially influence PK of 
tepotinib.
16.1.3
16.2
6
Overview of Planned Analyses
6.1
Interim Analysis
No interim analysis is planned for this trial.
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Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038  
       Final 1.0
C O N F I D E N T I A L
I N F O R M A T I O N
8/25
6.2
Final Analysis
The final, planned analyses identified in the Clinical Trial Protocol and in this IAP will be 
performed after the last subject has completed the last visit, i.e. end of trial visit/early termination 
visit with all trial data in-house, all data queries resolved, and the database locked. 
Nodatabase can be locked until this IAP has been approved.
7
Changes to the Planned Analyses in the Clinical Trial 
Protocol
The statistical methods as described in the protocol were adopted. 
8
Protocol Deviations and Analysis Sets
8.1
Definition of Protocol Deviations and Analysis Sets
Important protocol deviations are protocol deviations that might significantly affect the 
completeness, accuracy, and/or reliability of the trial data or that might significantly affect a 
subject's rights, safety, or well-being. 
No formal data review meeting will be held. However, the following deviations will be identified 
and confirmed before the database is locked: Important protocol deviations include

Deviations from the inclusion and exclusion criteria

Concomitant medication violations (see Section 6.5.1 of the protocol)

Use of prohibited medicines (see Section 6.5.2 of the protocol)

Subjects that receive incorrect treatment or dose

Sample processing errors that may lead to inaccurate bioanalytical results

Vomiting or diarrhea following oral dosing (these instances will be discussed on a case-
by-case basis)

Deviation from Good Clinical Practice

Non-compliance to trial procedures or deviations from trial procedures likely to affect the 
primary endpoints (e.g. subject develops withdrawal criteria whilst on the trial but is not 
withdrawn)

Deviation from trial medication compliance in terms of medical conditions and/or 
adverse events (AEs) that may have interfered with drug disposition or with respect to 
factors likely to affect the primary endpoints
Page 9 of 331


Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038  
       Final 1.0
C O N F I D E N T I A L
I N F O R M A T I O N
9/25
All important protocol deviations will be documented in Clinical Data Interchange Standard 
Consortium (CDISC) Study Data Tabulation Model (SDTM) datasets whether identified through 
sites monitoring or medical review. 
8.2
Definition of Analysis Sets
Analysis Set
Description
Screening
All subjects who signed informed consent.
Safety
The Safety Analysis Set will include all 
subjects who have received at least 1 dose of 
planned Investigational Medicinal Product
(IMP) and have had 1 subsequent safety 
assessment.
PK
The PK Analysis Set will include all subjects 
without any relevant protocol deviations with 
respect to PK and absence of factors likely to 
affect the comparability of PK results, with 
adequate trial medication compliance, and who 
have valid primary endpoints for both 
treatments.
Relevant decisions will be made before database lock.
9
General Specifications for Data Analyses
Statistical analyses will be performed using the computer program package SAS® System for 
Windows™ (Version 9.4 or later; SAS Institute, Cary, North Carolina, USA).
The results of this trial will be reported using summary tables, figures, and data listings, as 
appropriate. All data will be summarized overall and/or by treatment and/or by scheduled time 
point, as appropriate.
For demographic, baseline and safety assessments, continuous measurements will be 
summarized by means of descriptive statistics (i.e. number and percentage of observations, 
number and percentage of missing observations, mean, standard deviation [SD], median, the first 
and third quartile [Q1 and Q3], minimum [Min], and maximum [Max]) and categorical data will 
be summarized by means of frequency tables (i.e. count and percentages), if not stated otherwise. 
Mean, Median, Q1, Q3, Min, Max will have the same precision as the SDTM data (decimal 
places). SD will be presented with one decimal place more than the mean. For subject disposition 
and demographic tables the denominator will be the number of subjects in the analysis set. 
Counts of missing observations will be included as a separate category.
Page 10 of 331


Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038  
       Final 1.0
C O N F I D E N T I A L
I N F O R M A T I O N
10/25
Concentrations of tepotinib and its metabolites in plasma will be presented in tables and 
descriptively summarized by treatment and nominal time point using n, arithmetic mean, SD, 
standard error of the mean (SEM), median, minimum, maximum and CV%. Values below the 
lower limit of quantification (LLOQ) will be taken as zero for descriptive statistics of PK 
concentrations. Descriptive statistics of PK parameters will additionally show the geometric 
mean (GeoMean), the geometric coefficient of variation (GeoCV%), and the 95% CI for the 
GeoMean.
Graphical displays will be given, where appropriate. PK variables will be calculated and listed 
for all subjects who provide sufficient concentration-time data. Invalid data and their exclusion 
from statistical analysis will be discussed with the sponsor and flagged accordingly in the 
listings.
If not otherwise specified, ‘baseline’ refers to the last scheduled measurement before 
administration of the first drug in each period. 
However, if a subject is missing the baseline collection, the previous non-missing evaluation 
could become the baseline value (e.g. from screening/admission). If no baseline or previous to 
baseline evaluations exist, then the baseline value will be treated as missing.
The following calculations and derivations, as applicable, will be used: 
Change from baseline: post-baseline visit value - baseline value 
Duration of AE (in days hh:mm) = end date and time - start date and time of the AE, if 
missing time for either the beginning or end then = end date – start date + 1; in case of 
multiple records for the same AE, the duration will be calculated over all these records
Days hh:mm from dosing = start date and time of the event - date and time dose 
administration (for TEAEs); if missing time for either the dosing or event then = event start 
date – date of dose administration + 1
Rel. Day in period of AE = start date of the event – date of First Admin in period + 1 (for AEs 
on or after the day of dosing) 
Rel. Day in trial of AE = start date of the event – date of First Admin (for AEs before the day 
of dosing of the trial only) 
Repeated and unscheduled laboratory assessments will be included and flagged as repeats in the 
subject data listings, but not used  for summary tables statistics (unless the scheduled 
measurement was considered unreliable, e.g. due to technical reasons, and needed to be replaced 
by an unscheduled repeat measurement).
In this Phase I PK trial missing observations will be assumed to be missing completely at random 
(MCAR). No action will be taken to handle missing data. A subject who withdraws prior to the 
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Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038  
       Final 1.0
C O N F I D E N T I A L
I N F O R M A T I O N
11/25
last planned observation in a trial period will be included in the analyses up to the time of 
discontinuation.
The following treatment labels will be used:

5 x 100 mg TF3

2 x 250 mg TF3
Details of the statistical analysis will be provided in the subsequent sections. 
10
Trial Subjects
The subsections in this section include specifications for reporting subject disposition and 
treatment/trial discontinuations. Additionally, procedures for reporting protocol deviations are 
provided.
10.1
Disposition of Subjects and Discontinuations
The following will be presented in a summary table: 
Total number of subjects screened (i.e. subjects who gave informed consent)
Number of screened subjects who discontinued from the trial prior to treatment overall and 
grouped by the main reason for discontinuation:
o
Subject did not meet all eligibility criteria
o
Withdrew consent
o
Adverse event
o
Lost to follow-up
o
Death
o
Other 
Number of treated subjects by treatment and overall
Number and percentage of treated subjects who completed trial by treatment and overall
Number and percentage of treated subjects who discontinued the trial, with the primary reason 
of discontinuation by treatment and overall:
o
Adverse event
o
Lost to follow-up
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Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
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MS200095_0038  
       Final 1.0
C O N F I D E N T I A L
I N F O R M A T I O N
12/25
o
Protocol non-compliance
o
Death
o
Withdrew consent
o
Other
A listing of discontinued subjects will be provided.
10.2
Protocol Deviations
10.2.1
Important Protocol Deviations
Listings of important protocol deviations will be provided including the date and relative day in 
relation to dosing in the relevant period.
10.2.2
Reasons Leading to the Exclusion from an Analysis Set
All criteria/reasons leading to the exclusion of a subject from an analysis set (including clinically 
important protocol deviations) will be listed based on the safety set. 
Reasons for excluding individual PK concentrations will also be listed separately and flagged in 
the main listing based on the safety analysis set.
11
Demographics and Other Baseline Characteristics
11.1
Demographics
Summaries will be given for both the safety and the PK set, if different.
Demographic characteristics will be listed by subject and summarized using the following 
information from the Screening/Baseline Visit electronic Case Report From (eCRF) pages. 
Demographic characteristics:

Sex: male, female 

Race: Black or African American, American Indian or Alaska Native, Asian, Native 
Hawaiian or Pacific Islander, White, Other

Ethnic origin: Hispanic or Latino , Not Hispanic or Latino , Japanese, Not Japanese

Age (years): summary statistics

Height (cm) at Baseline: summary statistics
Page 13 of 331


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Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038  
       Final 1.0
C O N F I D E N T I A L
I N F O R M A T I O N
13/25

Weight (kg) at Baseline: summary statistics

BMI (kg/m²) at Baseline: summary statistics
Age will be taken from the eCRF and cannot be derived from the data because only the year of 
birth is collected in the eCRF.
BMI will be re-derived (i.e. not taken directly from the database) according to the following 
formula:
BMI (kg/m²) = weight (kg) / (height (m) * height (m))
11.2
Medical History
The medical history will be listed by subject including the preferred term (PT) and Medical 
Dictionary for Regulatory Activities (MedDRA) system organ class (SOC) body term using 
MedDRA latest version.
11.3
Other Baseline Characteristics
Other baseline characteristics will be listed by subject and summarized using the following 
information from the Screening/Baseline Visit eCRF pages. 
Other baseline characteristics:

Smoking status

Alcohol consumption
12
Previous or Concomitant Medications/Procedures
Previous medications are medications, other than trial medications and pre-medications for trial 
drug, which started and stopped before first administration of trial drug. 
Concomitant treatments are medications, other than trial medications, which are taken by 
subjects any time on-trial (on or after the first day of trial drug treatment for each subject). 
In case the date values will not allow to unequivocally allocate a medication to previous or 
concomitant medication the medication will be considered as concomitant medication.
Any previous and concomitant medication will be encoded with WHO-DD, latest version. Prior 
and concomitant medications will be listed by subject (all subjects).
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The following information will be displayed in a listing: generic or trade name (as reported in 
CRF), WHO drug name (including ATC-2nd level and PT), dose/unit, route, frequency, reason 
for use, start/end date and time.
Concomitant procedures will be presented in a data listing.
13
Treatment Compliance and Exposure
A listing of date and time of each drug administration and each blood sampling including time 
deviations will be provided sorted by subject.
14
Efficacy Analyses
Not applicable.
15
Safety Analyses
The subsections in this section include specifications for summarizing safety endpoints that are 
common across clinical trials such as adverse events, laboratory tests and vital signs.
Safety data analysis will be conducted on the Safety Analysis Set. 
15.1
Adverse Events
The number and percentage of subjects experiencing at least one TEAE will be summarized by 
treatment as well as the number of events. A TEAE is an AE with onset after start of treatment. 
Tables by relationship to trial drug and by severity will be generated. AEs will be coded using 
MedDRA terminology, latest version. 
If an event was reported more than once, the worst severity will be tabulated.
Incomplete TEAE-related dates will be flagged in listings and handled as follows:
In case the onset date is missing completely or missing partially but the onset month and year 
or the onset year are equal to the start of trial treatment, then the onset date will be replaced by 
the minimum of start of trial treatment and TEAE resolution date.
In all other cases the missing onset day or missing onset month will be replaced by 1.
Incomplete stop dates will be replaced by the last day of the month (if day is missing only), if 
not resulting in a date later than the date of subject's death. In the latter case, the date of death 
will be used to impute the incomplete stop date. 
In all other cases the incomplete stop date will not be imputed. 
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15.1.1
All Adverse Events
All AEs recorded during the course of the trial (i.e. assessed from signature of informed consent 
until the end of the Follow-up/End of Trial visit) will be coded according to MedDRA latest 
version and assigned to a SOC and PT.
TEAEs will be summarized by severity, using MedDRA latest version, with PT as event 
category and MedDRA primary SOC body term as body system category. The severity of AEs 
will be graded using the “National Cancer Institute - Common Terminology Criteria for Adverse 
Events” (NCI-CTCAE) guideline, version 5.0 (publication date: 27 Nov 2017), as detailed in the 
trial protocol.
TEAEs related to trial treatment are those events with relationship missing, unknown or related.
The following will be summarized in an overview table with the number and percentage of 
subjects (and the number of events) by treatment and overall:
Any TEAEs
Any trial treatment related TEAEs 
Any serious TEAEs 
Any trial treatment related serious TEAEs 
Any TEAE (grade >=3)
Any trial treatment related TEAEs (grade >=3) 
Any TEAEs leading to death
Any trial treatment related TEAEs leading to death
TEAEs will be summarized by treatment and overall in tables with:
The number and percentage of subjects by treatment with at least one TEAE and the number 
of events overall and by SOC and PT. Group/SOC terms will be sorted alphabetically and PTs 
within each group/SOC term will be sorted by descending frequency. 
The number and percentage of subjects by treatment with at least one non-serious TEAE and 
the number of non-serious TEAE applying frequency threshold of 5%. Group/SOC terms will 
be sorted alphabetically and PTs within each group/SOC term will be sorted by descending 
frequency.
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In addition the following tables will be provided. Group/SOC terms will be sorted alphabetically 
and PTs within each group/SOC term will be sorted by descending frequency (based on all 
treatment groups combined): 
A table by severity of TEAEs with the number and percentage of subjects by treatment with at 
least one TEAE and the number of events by SOC and PT. 
A table by relationship to trial treatment with the number and percentage of subjects by 
treatment with at least one TEAE and the number of events by SOC and PT. 
Pre-treatment AEs (AEs with onset after informed consent but before start of treatment) and 
TEAEs will be listed separately.
15.1.2
Adverse Events Leading to Treatment Discontinuation
TEAEs leading to permanent discontinuation of trial treatment will be summarized by treatment 
and overall including number of subjects, percentage and number of events.
A listing of TEAEs leading to permanent discontinuation of a trial treatment will additionally be 
provided.
15.2
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events
15.2.1
Deaths
All deaths as well as reason for death will be based on information from the “Report of Subject 
Death” CRFs. 
Listing of deaths, if any, will be provided displaying date and cause of death (including TEAE 
leading to death and relatedness to trial treatment, when applicable), and date and time of 
treatment administration.
15.2.2
Serious Adverse Events
A summary table of serious adverse events (SAEs), if any, by treatment and overall will be 
provided displaying the number and percentage of subjects by treatment with at least one SAE 
and the number of SAE overall and by system organ class and preferred term. Group/SOC terms 
and PTs within each group/SOC term will be sorted alphabetically.
Listing of SAEs, if any, will be provided in addition.
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15.2.3
Other Significant Adverse Event
15.2.3.1
Adverse Events of Special Interest
Healthy subjects might experience asymptomatic elevations in serum lipase and amylase. Any 
elevation in serum lipase and amylase of Grade ≥ 3 will lead to the recording of an adverse event 
of special interest (AESI). The severity of these AEs should be defined based on clinical 
judgment of the Investigator and defined according to NCI-CTCAE Severity Scale.
AESIs will be presented in a separate data listing.
15.3
Clinical Laboratory Evaluation
All laboratory data will be reported with SI units. Laboratory parameters will be listed by subject 
and time-point and summarized indicating the treatment at the respective time-point using 
descriptive statistics for absolute values and change from baseline over time and by post-dose 
CTCAE grade shift relative to baseline. Shift tables will be based on NCI-CTCAE grades, where 
possible, and on normal ranges otherwise. 
Shift tables will be presented for:
-
End of Trial/Follow-up versus Screening
-
Discharge Day 4 versus Pre-dose/Baseline (Tepotinib administration) within periods.
Laboratory values that are outside the normal range will also be flagged in the data listings, 
along with corresponding normal ranges and NCI-CTCAE grade. Any out-of-range values will 
additionally be listed separately including NCI-CTCAE grade. 
See section 7.4.3 of the clinical study protocol for a table of the safety laboratory evaluations.
Safety laboratory values are separated into:
Hematology
Biochemistry
Urinalysis
Other tests
Tables will be produced for the groups Hematology and Biochemistry.
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15.4
Vital Signs
Vital signs will be listed by subject and time-point and summarized for absolute values and 
changes-from-baseline (period-baseline) by visit and treatment using descriptive statistics. 
Descriptive statistics tables will start at baseline.
15.5
ECG Evaluation
Electrocardiogram (ECG) data will be listed by subject and time-point and summarized by 
absolute values and changes-from-baseline
(period-baseline)
by treatment
group using 
descriptive statistics. Baseline is the pre-dose assessment in each period. See section 9 for a 
description of how missing baseline values are handled. Descriptive statistics tables will start at 
baseline. Clinically significant ECG findings for individual subjects will be listed and 
summarized.
The time intervals (PR, QRS, RR, QT and corrected QT intervals [based on Fridericia’s formula, 
QTcF]) will be summarized descriptively by treatment. In case of triplicate ECGs, the mean of 
these measurements will be considered in summary tables.
The Fridericia’s Correction (QTcF) is derived as follows: 
Fridericia’s Correction (QTcF) 
where: RR = RR-interval measured in seconds.
QTcF values will be categorized according to their absolute values into the categories:
≤430 ms,
> 430 and ≤ 450 ms,
> 450 and ≤  480 ms,
> 480 and ≤  500 ms, and
> 500 ms,
and categorized according to their absolute change from period baseline into the categories:
≤30 ms,
> 30 and ≤  60 ms, and
> 60 ms.
3 RR
QT
QTc f 
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The number and percentage of subjects by these categories at any post-dose assessment will be 
tabulated by treatment group. All ECG measurements and changes from period baseline will be 
listed, with abnormalities (as reported of the Investigator on the ECG eCRF page) indicated.
Investigator reported interpretation results will also be tabulated by treatment using the number 
and percentage of subjects for each interpretation category (Normal, Abnormal Not Clinically 
Significant [NCS], Abnormal Clinically Significant [CS]).  In case of triplicate ECGs, the worst 
interpretation will be considered in these frequency tables.
16
Analyses of Other Endpoints
16.1
Pharmacokinetics
General Specifications for Plasma Concentration Data
Concentrations of tepotinib and its metabolites in plasma will be presented in tables and 
descriptively summarized by treatment and nominal time point using number of observations (n), 
Mean, SD, SEM, median, Min, Max, and CV%. Descriptive statistics of PK concentration data 
will be calculated using values with the same precision as the source data, and rounded for 
reporting purposes only. The following conventions will be applied when reporting descriptive 
statistics of PK concentration data:
Mean, Min, Median, Max: 
3 significant digits
SD, SEM:
4 significant digits
CV%:
1 decimal place 
Values below the LLOQ of the assay will be taken as zero for summary statistics of PK 
concentration data. For final evaluations values greater than the upper limit of quantification 
(ULOQ) are not accepted and should be replaced by valid numeric values from dilution 
measurement. Missing concentrations (e.g. no sample, insufficient sample volume for analysis, 
no result or result not valid) will be reported and used generally as “no result” (“N.R.”). Pre-dose 
samples that occur before the first drug administration will be assigned a time of 0 hours, as if 
the sample had been taken simultaneously with the study drug administration.
All available concentration data will be listed. Data of participants not in the PK analysis set or 
invalid data will be flagged accordingly. Any flags will be included in ADaM, respectively.
General Specifications for PK Parameter Data
PK parameter data will be descriptively summarized: n, Mean, SEM, SD, CV%, Min, median,
Max, geometric mean (GeoMean), the geometric coefficient of variation (GeoCV%) and the 
95% confidence interval for the GeoMean (LCI 95% GM, UCI 95% GM). 
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PK parameter Cmax will be reported with the same precision as the source data. All other PK 
parameters will be reported to 3 significant figures. In export datasets, as well as in the SDTM 
PP domain, PK parameters will be provided with full precision, and will not be rounded. 
Descriptive statistics of PK parameter data will be calculated using full precision values, and 
rounded for reporting purposes only. 
The following conventions will be applied when reporting descriptive statistics of PK parameter 
data:
Mean, Min, Median, Max, GeoMean, 95% CI: 
3 significant digits
SD, SEM:
4 significant digits
CV%, GeoCV%:
1 decimal place 
Ratio of GeoMean and 95% CI
4 decimal places
To ensure a reliable estimate of the extent of exposure, AUCextra should be less than or equal to 
20%. If AUCextra is greater than 20%, all parameters derived using λz (i.e. λz, t1/2, AUC0-
AUCextra, Vz/f, CL/F) will be listed, but set to missing for the calculation of descriptive statistics. 
All statistical analyses and descriptive summaries of PK data will be performed on the PK 
Analysis Set. All available concentration/PK data will be listed. Data of subjects not in the PK 
Analysis Set or invalid data will be flagged accordingly. Any flags will be included in ADaM, 
respectively.
16.1.1
Primary Endpoints
The primary endpoints will be descriptively summarized. Scatter plots will be produced for the 
individual PK parameters by treatment group indicating the geometric means within each 
treatment group.      
Statistical Hypotheses (Bioequivalence)
The following null hypothesis for the ratio of the geometric means will be used to assess 
bioequivalence:
H0:
µT/µR ≤ 0.8000 or 1.2500 ≤ µT/µR for at least one parameter (AUC0-t or 
AUC0-∞or Cmax)
H1:
0.8000 < µT/µR < 1.2500 for all parameters (AUC0-t and AUC0-∞and Cmax)
where µT and µR are the geometric means for the test and reference treatment respectively.
The test treatment is 5 tablets of the 100 mg dose strength of TF3 and reference is 2 tablets of the 
250 mg dose strength of TF3, both under fasting condition. 
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An analysis of variance (ANOVA) model with TREATMENT, PERIOD, SEQUENCE as fixed 
effects and SUBJECT(SEQUENCE) as random effect will be fitted to log-transformed primary 
endpoints AUC0-t, AUC0-∞and Cmax based on the PK analysis set.
Treatment differences 5 x 100 mg TF3 – 2 x 250 mg TF3 under fasting condition on the log scale 
will be estimated for Cmax, AUC0-t, and AUC0-∞together with their 90% CIs. Point estimates and 
CIs will be back-transformed to the original scale. 
The null hypothesis will be rejected if the 90% CI for the ratio of the geometric mean lies within 
the interval 0.8000 to 1.2500 for all parameters.
16.1.2
Secondary Endpoints 
The secondary PK endpoints will be descriptively summarized by treatment and listed. 
16.1.3
Exploratory Endpoints 
The PK endpoints AUC0-t, AUC0-∞, Cmax, tmax, t1/2 of tepotinib metabolites observed from time 
zero to 168 h post-dose of each period for the tepotinib metabolites MSC2571109A and 
MSC2571107A will be descriptively summarized by treatment and listed. 
Similar analyses as for the primary endpoints will be performed for the parameters based on the 
metabolites of tepotinib, using 90% CIs for the comparison 5 x 100 mg TF3 - 2 x 250 mg TF3, 
both under fasting condition.
The ANOVA model will have the same effects as the primary analysis applied to log-
transformed PK parameters Cmax, AUC0-t, and AUC0-∞.
A mixed model with TREATMENT, PERIOD, SEQUENCE as fixed effects and 
SUBJECT(SEQUENCE) as random effect will be applied.
16.1.4
Plasma Concentration Data
The following figures will be produced for the tepotinib and metabolites (MSC2571109A and 
MSC2571107A) plasma concentrations:
Arithmetic mean plasma concentration-time profiles overlaying all treatments on linear and 
semi-logarithmic scale
Arithmetic mean plasma concentration-time profiles overlaying all treatments on linear scale 
including SD error bars
Individual plasma concentration-time profiles overlaying subjects, for each treatment 
separately on linear and semi-logarithmic scale
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Individual plasma concentration-time profiles overlaying all treatments, separately for each 
subject on linear and semi-logarithmic scale
The following listings will be produced for the tepotinib and metabolites plasma concentrations:
Plasma concentrations will be listed by nominal time by treatment. Excluded plasma 
concentrations will be flagged.
16.1.5
Estimation of Individual Pharmacokinetic Parameters
The following non-compartmental PK parameters (see will be calculated from the individual 
plasma total tepotinib and metabolites concentration-time data using commercial software such 
as Phoenix®/WinNonlin® (Version 6.4 or higher) at Nuvisan GmbH.
Table 1
Definition of PK Parameters for Tepotinib and its Metabolites After Single 
Dose Administration
Symbol
Definition
AUC0-t
Area under the plasma concentration-time curve (AUC) from 
time zero (= dosing time) to the last sampling time (tlast) at 
which the concentration is at or above the lower limit of 
quantification (LLOQ), calculated using the mixed log linear 
trapezoidal rule (ie linear up/log down)
AUC0-t/D
AUC0-t divided by dose
AUC0-24
AUC from 0 to 24 hours, calculated using mixed log linear 
trapezoidal rule (linear up, log down)
AUC0-24/D
AUC0-24 divided by dose
AUC0-∞
AUC from time zero (= dosing time) extrapolated to infinity, 
calculated as AUC0-t + AUCextra. AUCextra represents the 
extrapolated part of AUC0-∞calculated by Clastpred/λz, where 
Clastpred is the predicted plasma concentration at the last 
sampling time point, calculated from the log-linear regression 
line for λz determination at which the measured plasma 
concentration is at or above LLOQ
AUC0-∞/D
AUC0-∞divided by dose
Cmax
Maximum plasma concentration observed
Cmax/D
Cmax divided by dose
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Symbol
Definition
tlast
The last sampling time at which the plasma concentration is at 
or above the lower limit of quantification
tmax
Time to reach the maximum observed plasma concentration
t1/2
Terminal half-life, calculated as ln(2)/λz
λz
Terminal rate constant determined from the terminal slope of 
the log-transformed plasma concentration curve using linear 
regression on terminal data points of the curve
CL/F
Apparent total body clearance of drug from plasma following 
extravascular administration, calculated as dose/AUC0-∞
Vz/f 
Apparent volume of distribution during the terminal phase 
following extravascular administration
AUCextra
The AUC from time tlast extrapolated to infinity
AUCextra%
AUCextra / AUC0-∞x 100.
Individual PK parameters will be calculated using actual sampling times. If the actual sampling 
time is missing, then the nominal sampling times will be used instead. The pre-dose sample will 
be considered as if it had been taken simultaneously with the administration of study drug. PK 
variables will be evaluated and listed for all subjects who provide sufficient concentration-time 
data.
Plasma concentrations below LLOQ willbe taken as zero for calculating the AUC. Plasma 
concentrations below LLOQ after the last quantifiable data point will not be considered for the 
determination of λz.
The following PK parameters will be calculated for diagnostic purposes and listed, but will not 
be summarized:

The time interval (h) of the log-linear regression (λz low, λz upp) to determine λz. 

Number of data points included in the log-linear regression analysis to determine λz.

Goodness of fit statistic (Rsq) for calculation of λz.  
The regression analysis should contain data from at least 3 different time points in the terminal 
phase consistent with the assessment of a straight line on the log-transformed scale. Phoenix 
WinNonlin best fit methodology will be used as standard. The last quantifiable concentration 
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should always be included in the regression analysis, while the concentration at tmax and any 
<LLOQ concentrations that occur after the last quantifiable data point should not be used. 
The coefficient of correlation (R²) should be ≥0.8 and the observation period over which the 
regression line is estimated should be at least twofold the resulting t1/2 itself. If these criteria are 
not met, then the corresponding values should be flagged in the listing displaying Individual 
Plasma Pharmacokinetic Diagnostic Parameters for Each Treatment. Any flags should be 
included in the study specific SDTM/ADaM. Then the rate constants and all derived parameters 
(e.g. AUC0-∞, %AUCextra, CL/f, t1/2, and VZ/f) will be included in the parameter listings and will 
be discussed appropriately in alignment with the protocol lead and quantitative pharmacology 
representative.
The following interpolation or extrapolation rules apply when calculating AUC0-24:

If the time point 24 hours falls within the time range in which samples were taken, but 
does not coincide with an observed data point, then a linear interpolation is performed to 
estimate the corresponding concentration value. 

If the time point 24 hours occurs after the last measurable concentration and the terminal 
regression (λz) is estimable, then λz is used to estimate the concentration at time 24 hours. 
If λz cannot be estimated the partial area will not be calculated.
The IMP dose administered is given for the monohydrate hydrochloride salt (i.e. 500 mg IMP). 
A conversion factor for the freebase IMP was calculated and will be applied when ‘dose’ is used 
in deriving PK parameter formulas needing a dose value (CL/f).
Conversion factor = Molecular weight (MW) of base IMP divided by MW of salt form IMP = 
492.574 g/mol / 547.05 g/mol = 0.9004 
Amount of dose * conversion factor = actual dose of IMP:  500 mg * 0.9004 = 450 mg
The Phoenix WinNonlin NCA Core Output will be provided in a separate listing.
16.2
Pharmacogenetics
Pharmacogenetic sampling is mandatory for trial participation. An additional separate ICF will 
be used. One blood sample should be collected in duplicate on Day -1 of the first treatment 
period prior to administration. The pharmacogenetic samples will be analyzed conditionally in 
case of unexpected PK profiles. The results of the PGx analysis, as applicable, will be described 
in a separate report.
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17
References
N.A.
18
Appendices
None.
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16.1.9.2: Statistical Analysis Output ............................................ 2 
Listing 16.1.9.2.1: Statistical Output of Primary Analysis.................... 3 
Listing 16.1.9.2.2: Statistical Output of Exploratory Analysis - Tepotinib 
Metabolite MSC2571109A....................................................... 21 
Listing 16.1.9.2.3: Statistical Output of Exploratory Analysis - Tepotinib 
Metabolite MSC2571107A....................................................... 39 
 
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16.1.9.2: Statistical Analysis Output 
 
 
Page 28 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.1: Statistical Output of Primary Analysis 
 
Parameter: AUC0-inf (h*ng/mL) for Tepotinib 
 
The Mixed Procedure 
 
                  Model Information 
 
Data Set                     WORK.PKPARS               
Dependent Variable           LOGAVAL                   
Covariance Structure         Variance Components       
Estimation Method            REML                      
Residual Variance Method     Profile                   
Fixed Effects SE Method      Model-Based               
Degrees of Freedom Method    Containment               
 
 
              Class Level Information 
  
Class       Levels    Values 
 
TRTA1            2    R T                            
APERIOD          2    1 2                            
  
  
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.12; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-prim-anova.sas, 28JAN2020 12:59                             Page 1 of 18 
 
 
Page 29 of 331


 
P r o t o c o l :  M S 2 0 0 0 9 5 - 0 0 3 8  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
1 6 . 1 :  S t u d y  I n f o r m a t i o n  
1 6 . 1 . 9 :  D o c u m e n t a t i o n  o f  S t a t i s t i c a l  M e t h o d s  
1 6 . 1 . 9 . 2 :  S t a t i s t i c a l  A n a l y s i s  O u t p u t  
L i s t i n g  1 6 . 1 . 9 . 2 . 1 :  S t a t i s t i c a l  O u t p u t  o f  P r i m a r y  A n a l y s i s  
 
P a r a m e t e r :  A U C 0 - i n f  ( h * n g / m L )  f o r  T e p o t i n i b  
 
T h e  M i x e d  P r o c e d u r e  
 
              C l a s s  L e v e l  I n f o r m a t i o n  
  
C l a s s        L e v e l s     V a l u e s  
 
U S U B J I D          1 8   
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
T :  5  x  1 0 0  m g  T F 3 ;  R :  2  x  2 5 0  m g  T F 3  
  
S o u r c e :  A D P P  2 2 J A N 2 0 2 0  1 3 : 5 5 ;  L i s t i n g  1 6 . 2 . 5 . 1 2 ;  S D T M  p a c k a g e :  1 5 J A N 2 0 2 0  
P r o g r a m :  J : \ B I O \ J 1 9 \ N - A - P H 1 - 1 9 - 0 7 0 \ t a b l e s \ t r - p r i m - a n o v a . s a s ,  2 8 J A N 2 0 2 0  1 2 : 5 9                              P a g e  2  o f  1 8  
 
 
Pa ge 3 0 of 3 3 1
PI


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.1: Statistical Output of Primary Analysis 
 
Parameter: AUC0-inf (h*ng/mL) for Tepotinib 
 
The Mixed Procedure 
 
              Class Level Information 
  
Class       Levels    Values 
 
SEQUENCE         2    RT TR                          
 
 
            Dimensions 
 
Covariance Parameters             2 
Columns in X                      7 
Columns in Z                     18 
Subjects                          1 
Max Obs Per Subject              35 
 
 
          Number of Observations 
 
Number of Observations Read              35 
Number of Observations Used              35 
Number of Observations Not Used           0 
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.12; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-prim-anova.sas, 28JAN2020 12:59                             Page 3 of 18 
 
 
Page 31 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.1: Statistical Output of Primary Analysis 
 
Parameter: AUC0-inf (h*ng/mL) for Tepotinib 
 
The Mixed Procedure 
 
                     Iteration History 
  
Iteration    Evaluations    -2 Res Log Like       Criterion 
 
        0              1        27.82729226                 
        1              2        14.18487139      0.00009191 
        2              1        14.18286276      0.00000010 
        3              1        14.18286061      0.00000000 
 
 
                   Convergence criteria met.                     
 
 
Covariance Parameter Estimates 
  
Cov Parm              Estimate 
 
USUBJID(SEQUENCE)      0.08236 
Residual               0.02311 
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.12; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-prim-anova.sas, 28JAN2020 12:59                             Page 4 of 18 
 
 
Page 32 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.1: Statistical Output of Primary Analysis 
 
Parameter: AUC0-inf (h*ng/mL) for Tepotinib 
 
The Mixed Procedure 
 
           Fit Statistics 
 
-2 Res Log Likelihood            14.2 
AIC (smaller is better)          18.2 
AICC (smaller is better)         18.6 
BIC (smaller is better)          20.0 
 
 
        Type 3 Tests of Fixed Effects 
  
              Num     Den 
Effect         DF      DF    F Value    Pr > F 
 
TRTA1           1      15       3.34    0.0875 
APERIOD         1      15       5.68    0.0308 
SEQUENCE        1      16       1.42    0.2502 
 
 
  
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.12; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-prim-anova.sas, 28JAN2020 12:59                             Page 5 of 18 
 
 
Page 33 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.1: Statistical Output of Primary Analysis 
 
Parameter: AUC0-inf (h*ng/mL) for Tepotinib 
 
The Mixed Procedure 
 
                                          Least Squares Means 
  
                               Standard 
Effect    TRTA1    Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper 
 
TRTA1     R          9.7527     0.07654      15     127.41      <.0001       0.1      9.6186      9.8869 
TRTA1     T          9.6576     0.07747      15     124.66      <.0001       0.1      9.5218      9.7934 
 
 
                                        Differences of Least Squares Means 
  
                                         Standard 
Effect    TRTA1    _TRTA1    Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper 
 
TRTA1     T        R         -0.09516     0.05206      15      -1.83      0.0875       0.1     -0.1864    -0.00390 
  
  
  
  
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.12; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-prim-anova.sas, 28JAN2020 12:59                             Page 6 of 18 
 
 
Page 34 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.1: Statistical Output of Primary Analysis 
 
Parameter: AUC0-t (h*ng/mL) for Tepotinib 
 
The Mixed Procedure 
 
                  Model Information 
 
Data Set                     WORK.PKPARS               
Dependent Variable           LOGAVAL                   
Covariance Structure         Variance Components       
Estimation Method            REML                      
Residual Variance Method     Profile                   
Fixed Effects SE Method      Model-Based               
Degrees of Freedom Method    Containment               
 
 
              Class Level Information 
  
Class       Levels    Values 
 
TRTA1            2    R T                            
APERIOD          2    1 2                            
  
  
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.12; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-prim-anova.sas, 28JAN2020 12:59                             Page 7 of 18 
 
 
Page 35 of 331


 
P r o t o c o l :  M S 2 0 0 0 9 5 - 0 0 3 8  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
1 6 . 1 :  S t u d y  I n f o r m a t i o n  
1 6 . 1 . 9 :  D o c u m e n t a t i o n  o f  S t a t i s t i c a l  M e t h o d s  
1 6 . 1 . 9 . 2 :  S t a t i s t i c a l  A n a l y s i s  O u t p u t  
L i s t i n g  1 6 . 1 . 9 . 2 . 1 :  S t a t i s t i c a l  O u t p u t  o f  P r i m a r y  A n a l y s i s  
 
P a r a m e t e r :  A U C 0 - t  ( h * n g / m L )  f o r  T e p o t i n i b  
 
T h e  M i x e d  P r o c e d u r e  
 
              C l a s s  L e v e l  I n f o r m a t i o n  
  
C l a s s        L e v e l s     V a l u e s  
 
U S U B J I D          1 8    
           
                     
           
                     
           
                     
           
                     
           
                     
           
                     
           
                     
           
                     
           
                     
           
                     
           
                     
           
                     
           
                     
           
                     
           
                     
           
                     
           
                     
           
  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
T :  5  x  1 0 0  m g  T F 3 ;  R :  2  x  2 5 0  m g  T F 3  
  
S o u r c e :  A D P P  2 2 J A N 2 0 2 0  1 3 : 5 5 ;  L i s t i n g  1 6 . 2 . 5 . 1 2 ;  S D T M  p a c k a g e :  1 5 J A N 2 0 2 0  
P r o g r a m :  J : \ B I O \ J 1 9 \ N - A - P H 1 - 1 9 - 0 7 0 \ t a b l e s \ t r - p r i m - a n o v a . s a s ,  2 8 J A N 2 0 2 0  1 2 : 5 9                              P a g e  8  o f  1 8  
 
 
Pa ge 3 6 of 3 3 1
PI


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.1: Statistical Output of Primary Analysis 
 
Parameter: AUC0-t (h*ng/mL) for Tepotinib 
 
The Mixed Procedure 
 
              Class Level Information 
  
Class       Levels    Values 
 
SEQUENCE         2    RT TR                          
 
 
            Dimensions 
 
Covariance Parameters             2 
Columns in X                      7 
Columns in Z                     18 
Subjects                          1 
Max Obs Per Subject              35 
 
 
          Number of Observations 
 
Number of Observations Read              35 
Number of Observations Used              35 
Number of Observations Not Used           0 
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.12; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-prim-anova.sas, 28JAN2020 12:59                             Page 9 of 18 
 
 
Page 37 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.1: Statistical Output of Primary Analysis 
 
Parameter: AUC0-t (h*ng/mL) for Tepotinib 
 
The Mixed Procedure 
 
                     Iteration History 
  
Iteration    Evaluations    -2 Res Log Like       Criterion 
 
        0              1        26.34579623                 
        1              2        13.26462856      0.00006316 
        2              1        13.26322330      0.00000005 
        3              1        13.26322224      0.00000000 
 
 
                   Convergence criteria met.                     
 
 
Covariance Parameter Estimates 
  
Cov Parm              Estimate 
 
USUBJID(SEQUENCE)      0.07738 
Residual               0.02303 
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.12; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-prim-anova.sas, 28JAN2020 12:59                            Page 10 of 18 
 
 
Page 38 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.1: Statistical Output of Primary Analysis 
 
Parameter: AUC0-t (h*ng/mL) for Tepotinib 
 
The Mixed Procedure 
 
           Fit Statistics 
 
-2 Res Log Likelihood            13.3 
AIC (smaller is better)          17.3 
AICC (smaller is better)         17.7 
BIC (smaller is better)          19.0 
 
 
        Type 3 Tests of Fixed Effects 
  
              Num     Den 
Effect         DF      DF    F Value    Pr > F 
 
TRTA1           1      15       3.18    0.0947 
APERIOD         1      15       6.09    0.0261 
SEQUENCE        1      16       1.40    0.2546 
 
 
  
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.12; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-prim-anova.sas, 28JAN2020 12:59                            Page 11 of 18 
 
 
Page 39 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.1: Statistical Output of Primary Analysis 
 
Parameter: AUC0-t (h*ng/mL) for Tepotinib 
 
The Mixed Procedure 
 
                                          Least Squares Means 
  
                               Standard 
Effect    TRTA1    Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper 
 
TRTA1     R          9.7125     0.07469      15     130.04      <.0001       0.1      9.5816      9.8434 
TRTA1     T          9.6198     0.07563      15     127.19      <.0001       0.1      9.4872      9.7524 
 
 
                                        Differences of Least Squares Means 
  
                                         Standard 
Effect    TRTA1    _TRTA1    Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper 
 
TRTA1     T        R         -0.09269     0.05197      15      -1.78      0.0947       0.1     -0.1838    -0.00159 
  
  
  
  
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.12; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-prim-anova.sas, 28JAN2020 12:59                            Page 12 of 18 
 
 
Page 40 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.1: Statistical Output of Primary Analysis 
 
Parameter: Cmax (ng/mL) for Tepotinib 
 
The Mixed Procedure 
 
                  Model Information 
 
Data Set                     WORK.PKPARS               
Dependent Variable           LOGAVAL                   
Covariance Structure         Variance Components       
Estimation Method            REML                      
Residual Variance Method     Profile                   
Fixed Effects SE Method      Model-Based               
Degrees of Freedom Method    Containment               
 
 
              Class Level Information 
  
Class       Levels    Values 
 
TRTA1            2    R T                            
APERIOD          2    1 2                            
  
  
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.12; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-prim-anova.sas, 28JAN2020 12:59                            Page 13 of 18 
 
 
Page 41 of 331


 
P r o t o c o l :  M S 2 0 0 0 9 5 - 0 0 3 8  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
1 6 . 1 :  S t u d y  I n f o r m a t i o n  
1 6 . 1 . 9 :  D o c u m e n t a t i o n  o f  S t a t i s t i c a l  M e t h o d s  
1 6 . 1 . 9 . 2 :  S t a t i s t i c a l  A n a l y s i s  O u t p u t  
L i s t i n g  1 6 . 1 . 9 . 2 . 1 :  S t a t i s t i c a l  O u t p u t  o f  P r i m a r y  A n a l y s i s  
 
P a r a m e t e r :  C m a x  ( n g / m L )  f o r  T e p o t i n i b  
 
T h e  M i x e d  P r o c e d u r e  
 
              C l a s s  L e v e l  I n f o r m a t i o n  
  
C l a s s        L e v e l s     V a l u e s  
 
U S U B J I D          1 8   
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
T :  5  x  1 0 0  m g  T F 3 ;  R :  2  x  2 5 0  m g  T F 3  
  
S o u r c e :  A D P P  2 2 J A N 2 0 2 0  1 3 : 5 5 ;  L i s t i n g  1 6 . 2 . 5 . 1 2 ;  S D T M  p a c k a g e :  1 5 J A N 2 0 2 0  
P r o g r a m :  J : \ B I O \ J 1 9 \ N - A - P H 1 - 1 9 - 0 7 0 \ t a b l e s \ t r - p r i m - a n o v a . s a s ,  2 8 J A N 2 0 2 0  1 2 : 5 9                             P a g e  1 4  o f  1 8  
 
 
Pa ge 4 2 of 3 3 1
PI


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.1: Statistical Output of Primary Analysis 
 
Parameter: Cmax (ng/mL) for Tepotinib 
 
The Mixed Procedure 
 
              Class Level Information 
  
Class       Levels    Values 
 
SEQUENCE         2    RT TR                          
 
 
            Dimensions 
 
Covariance Parameters             2 
Columns in X                      7 
Columns in Z                     18 
Subjects                          1 
Max Obs Per Subject              36 
 
 
          Number of Observations 
 
Number of Observations Read              36 
Number of Observations Used              36 
Number of Observations Not Used           0 
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.12; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-prim-anova.sas, 28JAN2020 12:59                            Page 15 of 18 
 
 
Page 43 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.1: Statistical Output of Primary Analysis 
 
Parameter: Cmax (ng/mL) for Tepotinib 
 
The Mixed Procedure 
 
                     Iteration History 
  
Iteration    Evaluations    -2 Res Log Like       Criterion 
 
        0              1         7.31480767                 
        1              1         2.58411332      0.00000000 
 
 
                   Convergence criteria met.                     
 
 
Covariance Parameter Estimates 
  
Cov Parm              Estimate 
 
USUBJID(SEQUENCE)      0.02709 
Residual               0.02645 
 
 
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.12; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-prim-anova.sas, 28JAN2020 12:59                            Page 16 of 18 
 
 
Page 44 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.1: Statistical Output of Primary Analysis 
 
Parameter: Cmax (ng/mL) for Tepotinib 
 
The Mixed Procedure 
 
           Fit Statistics 
 
-2 Res Log Likelihood             2.6 
AIC (smaller is better)           6.6 
AICC (smaller is better)          7.0 
BIC (smaller is better)           8.4 
 
 
        Type 3 Tests of Fixed Effects 
  
              Num     Den 
Effect         DF      DF    F Value    Pr > F 
 
TRTA1           1      16       0.69    0.4173 
APERIOD         1      16       3.61    0.0754 
SEQUENCE        1      16       0.38    0.5462 
 
 
  
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.12; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-prim-anova.sas, 28JAN2020 12:59                            Page 17 of 18 
 
 
Page 45 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.1: Statistical Output of Primary Analysis 
 
Parameter: Cmax (ng/mL) for Tepotinib 
 
The Mixed Procedure 
 
                                          Least Squares Means 
  
                               Standard 
Effect    TRTA1    Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper 
 
TRTA1     R          5.4826     0.05454      16     100.52      <.0001       0.1      5.3874      5.5778 
TRTA1     T          5.5277     0.05454      16     101.35      <.0001       0.1      5.4325      5.6230 
 
 
                                        Differences of Least Squares Means 
  
                                         Standard 
Effect    TRTA1    _TRTA1    Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper 
 
TRTA1     T        R          0.04515     0.05422      16       0.83      0.4173       0.1    -0.04951      0.1398 
  
  
  
  
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.12; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-prim-anova.sas, 28JAN2020 12:59                            Page 18 of 18 
 
 
Page 46 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.2: Statistical Output of Exploratory Analysis - Tepotinib Metabolite MSC2571109A 
 
Parameter: AUC0-inf (h*ng/mL) for Metabolite MSC2571109A 
 
The Mixed Procedure 
 
                  Model Information 
 
Data Set                     WORK.PKPARS               
Dependent Variable           LOGAVAL                   
Covariance Structure         Variance Components       
Estimation Method            REML                      
Residual Variance Method     Profile                   
Fixed Effects SE Method      Model-Based               
Degrees of Freedom Method    Containment               
 
 
              Class Level Information 
  
Class       Levels    Values 
 
TRTA1            2    R T                            
APERIOD          2    1 2                            
  
  
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.13; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-expl-anova.sas, 28JAN2020 13:02                             Page 1 of 18 
 
 
Page 47 of 331


 
P r o t o c o l :  M S 2 0 0 0 9 5 - 0 0 3 8  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
1 6 . 1 :  S t u d y  I n f o r m a t i o n  
1 6 . 1 . 9 :  D o c u m e n t a t i o n  o f  S t a t i s t i c a l  M e t h o d s  
1 6 . 1 . 9 . 2 :  S t a t i s t i c a l  A n a l y s i s  O u t p u t  
L i s t i n g  1 6 . 1 . 9 . 2 . 2 :  S t a t i s t i c a l  O u t p u t  o f  E x p l o r a t o r y  A n a l y s i s  -  T e p o t i n i b  M e t a b o l i t e  M S C 2 5 7 1 1 0 9 A  
 
P a r a m e t e r :  A U C 0 - i n f  ( h * n g / m L )  f o r  M e t a b o l i t e  M S C 2 5 7 1 1 0 9 A  
 
T h e  M i x e d  P r o c e d u r e  
 
              C l a s s  L e v e l  I n f o r m a t i o n  
  
C l a s s        L e v e l s     V a l u e s  
 
U S U B J I D          1 8   
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
T :  5  x  1 0 0  m g  T F 3 ;  R :  2  x  2 5 0  m g  T F 3  
  
S o u r c e :  A D P P  2 2 J A N 2 0 2 0  1 3 : 5 5 ;  L i s t i n g  1 6 . 2 . 5 . 1 3 ;  S D T M  p a c k a g e :  1 5 J A N 2 0 2 0  
P r o g r a m :  J : \ B I O \ J 1 9 \ N - A - P H 1 - 1 9 - 0 7 0 \ t a b l e s \ t r - e x p l - a n o v a . s a s ,  2 8 J A N 2 0 2 0  1 3 : 0 2                              P a g e  2  o f  1 8  
 
 
Pa ge 4 8 of 3 3 1
PI


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.2: Statistical Output of Exploratory Analysis - Tepotinib Metabolite MSC2571109A 
 
Parameter: AUC0-inf (h*ng/mL) for Metabolite MSC2571109A 
 
The Mixed Procedure 
 
              Class Level Information 
  
Class       Levels    Values 
 
SEQUENCE         2    RT TR                          
 
 
            Dimensions 
 
Covariance Parameters             2 
Columns in X                      7 
Columns in Z                     18 
Subjects                          1 
Max Obs Per Subject              35 
 
 
          Number of Observations 
 
Number of Observations Read              35 
Number of Observations Used              34 
Number of Observations Not Used           1 
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.13; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-expl-anova.sas, 28JAN2020 13:02                             Page 3 of 18 
 
 
Page 49 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.2: Statistical Output of Exploratory Analysis - Tepotinib Metabolite MSC2571109A 
 
Parameter: AUC0-inf (h*ng/mL) for Metabolite MSC2571109A 
 
The Mixed Procedure 
 
                     Iteration History 
  
Iteration    Evaluations    -2 Res Log Like       Criterion 
 
        0              1        31.53030633                 
        1              2        16.76697914      0.00007090 
        2              1        16.76559433      0.00000005 
        3              1        16.76559328      0.00000000 
 
 
                   Convergence criteria met.                     
 
 
Covariance Parameter Estimates 
  
Cov Parm              Estimate 
 
USUBJID(SEQUENCE)      0.09898 
Residual               0.02278 
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.13; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-expl-anova.sas, 28JAN2020 13:02                             Page 4 of 18 
 
 
Page 50 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.2: Statistical Output of Exploratory Analysis - Tepotinib Metabolite MSC2571109A 
 
Parameter: AUC0-inf (h*ng/mL) for Metabolite MSC2571109A 
 
The Mixed Procedure 
 
           Fit Statistics 
 
-2 Res Log Likelihood            16.8 
AIC (smaller is better)          20.8 
AICC (smaller is better)         21.2 
BIC (smaller is better)          22.5 
 
 
        Type 3 Tests of Fixed Effects 
  
              Num     Den 
Effect         DF      DF    F Value    Pr > F 
 
TRTA1           1      14       2.11    0.1685 
APERIOD         1      14       3.75    0.0731 
SEQUENCE        1      16       0.71    0.4120 
 
 
  
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.13; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-expl-anova.sas, 28JAN2020 13:02                             Page 5 of 18 
 
 
Page 51 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.2: Statistical Output of Exploratory Analysis - Tepotinib Metabolite MSC2571109A 
 
Parameter: AUC0-inf (h*ng/mL) for Metabolite MSC2571109A 
 
The Mixed Procedure 
 
                                          Least Squares Means 
  
                               Standard 
Effect    TRTA1    Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper 
 
TRTA1     R          9.3035     0.08311      14     111.94      <.0001       0.1      9.1571      9.4499 
TRTA1     T          9.2264     0.08311      14     111.01      <.0001       0.1      9.0801      9.3728 
 
 
                                        Differences of Least Squares Means 
  
                                         Standard 
Effect    TRTA1    _TRTA1    Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper 
 
TRTA1     T        R         -0.07708     0.05308      14      -1.45      0.1685       0.1     -0.1706     0.01641 
  
  
  
  
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.13; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-expl-anova.sas, 28JAN2020 13:02                             Page 6 of 18 
 
 
Page 52 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.2: Statistical Output of Exploratory Analysis - Tepotinib Metabolite MSC2571109A 
 
Parameter: AUC0-t (h*ng/mL) for Metabolite MSC2571109A 
 
The Mixed Procedure 
 
                  Model Information 
 
Data Set                     WORK.PKPARS               
Dependent Variable           LOGAVAL                   
Covariance Structure         Variance Components       
Estimation Method            REML                      
Residual Variance Method     Profile                   
Fixed Effects SE Method      Model-Based               
Degrees of Freedom Method    Containment               
 
 
              Class Level Information 
  
Class       Levels    Values 
 
TRTA1            2    R T                            
APERIOD          2    1 2                            
  
  
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.13; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-expl-anova.sas, 28JAN2020 13:02                             Page 7 of 18 
 
 
Page 53 of 331


 
P r o t o c o l :  M S 2 0 0 0 9 5 - 0 0 3 8  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
1 6 . 1 :  S t u d y  I n f o r m a t i o n  
1 6 . 1 . 9 :  D o c u m e n t a t i o n  o f  S t a t i s t i c a l  M e t h o d s  
1 6 . 1 . 9 . 2 :  S t a t i s t i c a l  A n a l y s i s  O u t p u t  
L i s t i n g  1 6 . 1 . 9 . 2 . 2 :  S t a t i s t i c a l  O u t p u t  o f  E x p l o r a t o r y  A n a l y s i s  -  T e p o t i n i b  M e t a b o l i t e  M S C 2 5 7 1 1 0 9 A  
 
P a r a m e t e r :  A U C 0 - t  ( h * n g / m L )  f o r  M e t a b o l i t e  M S C 2 5 7 1 1 0 9 A  
 
T h e  M i x e d  P r o c e d u r e  
 
              C l a s s  L e v e l  I n f o r m a t i o n  
  
C l a s s        L e v e l s     V a l u e s  
 
U S U B J I D          1 8   
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
                    
           
  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
T :  5  x  1 0 0  m g  T F 3 ;  R :  2  x  2 5 0  m g  T F 3  
  
S o u r c e :  A D P P  2 2 J A N 2 0 2 0  1 3 : 5 5 ;  L i s t i n g  1 6 . 2 . 5 . 1 3 ;  S D T M  p a c k a g e :  1 5 J A N 2 0 2 0  
P r o g r a m :  J : \ B I O \ J 1 9 \ N - A - P H 1 - 1 9 - 0 7 0 \ t a b l e s \ t r - e x p l - a n o v a . s a s ,  2 8 J A N 2 0 2 0  1 3 : 0 2                              P a g e  8  o f  1 8  
 
 
Pa ge 5 4 of 3 3 1
PI


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.2: Statistical Output of Exploratory Analysis - Tepotinib Metabolite MSC2571109A 
 
Parameter: AUC0-t (h*ng/mL) for Metabolite MSC2571109A 
 
The Mixed Procedure 
 
              Class Level Information 
  
Class       Levels    Values 
 
SEQUENCE         2    RT TR                          
 
 
            Dimensions 
 
Covariance Parameters             2 
Columns in X                      7 
Columns in Z                     18 
Subjects                          1 
Max Obs Per Subject              35 
 
 
          Number of Observations 
 
Number of Observations Read              35 
Number of Observations Used              35 
Number of Observations Not Used           0 
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.13; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-expl-anova.sas, 28JAN2020 13:02                             Page 9 of 18 
 
 
Page 55 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.2: Statistical Output of Exploratory Analysis - Tepotinib Metabolite MSC2571109A 
 
Parameter: AUC0-t (h*ng/mL) for Metabolite MSC2571109A 
 
The Mixed Procedure 
 
                     Iteration History 
  
Iteration    Evaluations    -2 Res Log Like       Criterion 
 
        0              1        26.81517413                 
        1              2        11.88675358      0.00035958 
        2              1        11.87830803      0.00000157 
        3              1        11.87827247      0.00000000 
 
 
                   Convergence criteria met.                     
 
 
Covariance Parameter Estimates 
  
Cov Parm              Estimate 
 
USUBJID(SEQUENCE)      0.08272 
Residual               0.02009 
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.13; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-expl-anova.sas, 28JAN2020 13:02                            Page 10 of 18 
 
 
Page 56 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.2: Statistical Output of Exploratory Analysis - Tepotinib Metabolite MSC2571109A 
 
Parameter: AUC0-t (h*ng/mL) for Metabolite MSC2571109A 
 
The Mixed Procedure 
 
           Fit Statistics 
 
-2 Res Log Likelihood            11.9 
AIC (smaller is better)          15.9 
AICC (smaller is better)         16.3 
BIC (smaller is better)          17.7 
 
 
        Type 3 Tests of Fixed Effects 
  
              Num     Den 
Effect         DF      DF    F Value    Pr > F 
 
TRTA1           1      15       2.29    0.1511 
APERIOD         1      15       4.59    0.0491 
SEQUENCE        1      16       0.68    0.4226 
 
 
  
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.13; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-expl-anova.sas, 28JAN2020 13:02                            Page 11 of 18 
 
 
Page 57 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.2: Statistical Output of Exploratory Analysis - Tepotinib Metabolite MSC2571109A 
 
Parameter: AUC0-t (h*ng/mL) for Metabolite MSC2571109A 
 
The Mixed Procedure 
 
                                          Least Squares Means 
  
                               Standard 
Effect    TRTA1    Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper 
 
TRTA1     R          9.2341     0.07558      15     122.18      <.0001       0.1      9.1016      9.3666 
TRTA1     T          9.1606     0.07641      15     119.90      <.0001       0.1      9.0267      9.2946 
 
 
                                        Differences of Least Squares Means 
  
                                         Standard 
Effect    TRTA1    _TRTA1    Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper 
 
TRTA1     T        R         -0.07348     0.04856      15      -1.51      0.1511       0.1     -0.1586     0.01166 
  
  
  
  
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.13; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-expl-anova.sas, 28JAN2020 13:02                            Page 12 of 18 
 
 
Page 58 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.2: Statistical Output of Exploratory Analysis - Tepotinib Metabolite MSC2571109A 
 
Parameter: Cmax (ng/mL) for Metabolite MSC2571109A 
 
The Mixed Procedure 
 
                  Model Information 
 
Data Set                     WORK.PKPARS               
Dependent Variable           LOGAVAL                   
Covariance Structure         Variance Components       
Estimation Method            REML                      
Residual Variance Method     Profile                   
Fixed Effects SE Method      Model-Based               
Degrees of Freedom Method    Containment               
 
 
              Class Level Information 
  
Class       Levels    Values 
 
TRTA1            2    R T                            
APERIOD          2    1 2                            
  
  
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.13; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-expl-anova.sas, 28JAN2020 13:02                            Page 13 of 18 
 
 
Page 59 of 331


 
P r o t o c o l :  M S 2 0 0 0 9 5 - 0 0 3 8  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
1 6 . 1 :  S t u d y  I n f o r m a t i o n  
1 6 . 1 . 9 :  D o c u m e n t a t i o n  o f  S t a t i s t i c a l  M e t h o d s  
1 6 . 1 . 9 . 2 :  S t a t i s t i c a l  A n a l y s i s  O u t p u t  
L i s t i n g  1 6 . 1 . 9 . 2 . 2 :  S t a t i s t i c a l  O u t p u t  o f  E x p l o r a t o r y  A n a l y s i s  -  T e p o t i n i b  M e t a b o l i t e  M S C 2 5 7 1 1 0 9 A  
 
P a r a m e t e r :  C m a x  ( n g / m L )  f o r  M e t a b o l i t e  M S C 2 5 7 1 1 0 9 A  
 
T h e  M i x e d  P r o c e d u r e  
 
              C l a s s  L e v e l  I n f o r m a t i o n  
  
C l a s s        L e v e l s     V a l u e s  
 
U S U B J I D          1 8   
             
                    
             
                    
             
                    
             
                    
             
                    
             
                    
             
                    
             
                    
             
                    
             
                    
             
                    
             
                    
             
                    
             
                    
             
                    
             
                    
             
                    
             
  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
T :  5  x  1 0 0  m g  T F 3 ;  R :  2  x  2 5 0  m g  T F 3  
  
S o u r c e :  A D P P  2 2 J A N 2 0 2 0  1 3 : 5 5 ;  L i s t i n g  1 6 . 2 . 5 . 1 3 ;  S D T M  p a c k a g e :  1 5 J A N 2 0 2 0  
P r o g r a m :  J : \ B I O \ J 1 9 \ N - A - P H 1 - 1 9 - 0 7 0 \ t a b l e s \ t r - e x p l - a n o v a . s a s ,  2 8 J A N 2 0 2 0  1 3 : 0 2                             P a g e  1 4  o f  1 8  
 
 
Pa ge 6 0 of 3 3 1
PI


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.2: Statistical Output of Exploratory Analysis - Tepotinib Metabolite MSC2571109A 
 
Parameter: Cmax (ng/mL) for Metabolite MSC2571109A 
 
The Mixed Procedure 
 
              Class Level Information 
  
Class       Levels    Values 
 
SEQUENCE         2    RT TR                          
 
 
            Dimensions 
 
Covariance Parameters             2 
Columns in X                      7 
Columns in Z                     18 
Subjects                          1 
Max Obs Per Subject              36 
 
 
          Number of Observations 
 
Number of Observations Read              36 
Number of Observations Used              36 
Number of Observations Not Used           0 
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.13; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-expl-anova.sas, 28JAN2020 13:02                            Page 15 of 18 
 
 
Page 61 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.2: Statistical Output of Exploratory Analysis - Tepotinib Metabolite MSC2571109A 
 
Parameter: Cmax (ng/mL) for Metabolite MSC2571109A 
 
The Mixed Procedure 
 
                     Iteration History 
  
Iteration    Evaluations    -2 Res Log Like       Criterion 
 
        0              1        15.17122702                 
        1              1         6.48385334      0.00000000 
 
 
                   Convergence criteria met.                     
 
 
Covariance Parameter Estimates 
  
Cov Parm              Estimate 
 
USUBJID(SEQUENCE)      0.04430 
Residual               0.02414 
 
 
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.13; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-expl-anova.sas, 28JAN2020 13:02                            Page 16 of 18 
 
 
Page 62 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.2: Statistical Output of Exploratory Analysis - Tepotinib Metabolite MSC2571109A 
 
Parameter: Cmax (ng/mL) for Metabolite MSC2571109A 
 
The Mixed Procedure 
 
           Fit Statistics 
 
-2 Res Log Likelihood             6.5 
AIC (smaller is better)          10.5 
AICC (smaller is better)         10.9 
BIC (smaller is better)          12.3 
 
 
        Type 3 Tests of Fixed Effects 
  
              Num     Den 
Effect         DF      DF    F Value    Pr > F 
 
TRTA1           1      16       0.19    0.6704 
APERIOD         1      16       4.23    0.0563 
SEQUENCE        1      16       0.33    0.5736 
 
 
  
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.13; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-expl-anova.sas, 28JAN2020 13:02                            Page 17 of 18 
 
 
Page 63 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.2: Statistical Output of Exploratory Analysis - Tepotinib Metabolite MSC2571109A 
 
Parameter: Cmax (ng/mL) for Metabolite MSC2571109A 
 
The Mixed Procedure 
 
                                          Least Squares Means 
  
                               Standard 
Effect    TRTA1    Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper 
 
TRTA1     R          4.7859     0.06166      16      77.61      <.0001       0.1      4.6782      4.8935 
TRTA1     T          4.7634     0.06166      16      77.25      <.0001       0.1      4.6558      4.8711 
 
 
                                        Differences of Least Squares Means 
  
                                         Standard 
Effect    TRTA1    _TRTA1    Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper 
 
TRTA1     T        R         -0.02246     0.05179      16      -0.43      0.6704       0.1     -0.1129     0.06796 
  
  
  
  
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.13; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-expl-anova.sas, 28JAN2020 13:02                            Page 18 of 18 
 
 
Page 64 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.3: Statistical Output of Exploratory Analysis - Tepotinib Metabolite MSC2571107A 
 
Parameter: AUC0-inf (h*ng/mL) for Metabolite MSC2571107A 
 
The Mixed Procedure 
 
                  Model Information 
 
Data Set                     WORK.PKPARS               
Dependent Variable           LOGAVAL                   
Covariance Structure         Variance Components       
Estimation Method            REML                      
Residual Variance Method     Profile                   
Fixed Effects SE Method      Model-Based               
Degrees of Freedom Method    Containment               
 
 
              Class Level Information 
  
Class       Levels    Values 
 
TRTA1            2    R T                            
APERIOD          2    1 2                            
  
  
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.14; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-expl-anova.sas, 28JAN2020 13:02                             Page 1 of 18 
 
 
Page 65 of 331


 
P r o t o c o l :  M S 2 0 0 0 9 5 - 0 0 3 8  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
1 6 . 1 :  S t u d y  I n f o r m a t i o n  
1 6 . 1 . 9 :  D o c u m e n t a t i o n  o f  S t a t i s t i c a l  M e t h o d s  
1 6 . 1 . 9 . 2 :  S t a t i s t i c a l  A n a l y s i s  O u t p u t  
L i s t i n g  1 6 . 1 . 9 . 2 . 3 :  S t a t i s t i c a l  O u t p u t  o f  E x p l o r a t o r y  A n a l y s i s  -  T e p o t i n i b  M e t a b o l i t e  M S C 2 5 7 1 1 0 7 A  
 
P a r a m e t e r :  A U C 0 - i n f  ( h * n g / m L )  f o r  M e t a b o l i t e  M S C 2 5 7 1 1 0 7 A  
 
T h e  M i x e d  P r o c e d u r e  
 
              C l a s s  L e v e l  I n f o r m a t i o n  
  
C l a s s        L e v e l s     V a l u e s  
 
U S U B J I D          1 8    
           
                     
           
                     
           
                     
           
                     
           
                     
           
                     
           
                     
           
                     
           
                     
           
                     
           
                     
           
                     
           
                     
           
                     
           
                     
           
                     
           
                     
           
  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
T :  5  x  1 0 0  m g  T F 3 ;  R :  2  x  2 5 0  m g  T F 3  
  
S o u r c e :  A D P P  2 2 J A N 2 0 2 0  1 3 : 5 5 ;  L i s t i n g  1 6 . 2 . 5 . 1 4 ;  S D T M  p a c k a g e :  1 5 J A N 2 0 2 0  
P r o g r a m :  J : \ B I O \ J 1 9 \ N - A - P H 1 - 1 9 - 0 7 0 \ t a b l e s \ t r - e x p l - a n o v a . s a s ,  2 8 J A N 2 0 2 0  1 3 : 0 2                              P a g e  2  o f  1 8  
 
 
Pa ge 6 6 of 3 3 1
PI


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.3: Statistical Output of Exploratory Analysis - Tepotinib Metabolite MSC2571107A 
 
Parameter: AUC0-inf (h*ng/mL) for Metabolite MSC2571107A 
 
The Mixed Procedure 
 
              Class Level Information 
  
Class       Levels    Values 
 
SEQUENCE         2    RT TR                          
 
 
            Dimensions 
 
Covariance Parameters             2 
Columns in X                      7 
Columns in Z                     18 
Subjects                          1 
Max Obs Per Subject              35 
 
 
          Number of Observations 
 
Number of Observations Read              35 
Number of Observations Used              34 
Number of Observations Not Used           1 
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.14; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-expl-anova.sas, 28JAN2020 13:02                             Page 3 of 18 
 
 
Page 67 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.3: Statistical Output of Exploratory Analysis - Tepotinib Metabolite MSC2571107A 
 
Parameter: AUC0-inf (h*ng/mL) for Metabolite MSC2571107A 
 
The Mixed Procedure 
 
                     Iteration History 
  
Iteration    Evaluations    -2 Res Log Like       Criterion 
 
        0              1        39.33425405                 
        1              3        22.75268267      0.00020766 
        2              1        22.74922662      0.00000039 
        3              1        22.74922033      0.00000000 
 
 
                   Convergence criteria met.                     
 
 
Covariance Parameter Estimates 
  
Cov Parm              Estimate 
 
USUBJID(SEQUENCE)       0.1279 
Residual               0.02641 
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.14; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-expl-anova.sas, 28JAN2020 13:02                             Page 4 of 18 
 
 
Page 68 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.3: Statistical Output of Exploratory Analysis - Tepotinib Metabolite MSC2571107A 
 
Parameter: AUC0-inf (h*ng/mL) for Metabolite MSC2571107A 
 
The Mixed Procedure 
 
           Fit Statistics 
 
-2 Res Log Likelihood            22.7 
AIC (smaller is better)          26.7 
AICC (smaller is better)         27.2 
BIC (smaller is better)          28.5 
 
 
        Type 3 Tests of Fixed Effects 
  
              Num     Den 
Effect         DF      DF    F Value    Pr > F 
 
TRTA1           1      14       1.97    0.1821 
APERIOD         1      14       3.43    0.0854 
SEQUENCE        1      16       1.19    0.2917 
 
 
  
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.14; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-expl-anova.sas, 28JAN2020 13:02                             Page 5 of 18 
 
 
Page 69 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.3: Statistical Output of Exploratory Analysis - Tepotinib Metabolite MSC2571107A 
 
Parameter: AUC0-inf (h*ng/mL) for Metabolite MSC2571107A 
 
The Mixed Procedure 
 
                                          Least Squares Means 
  
                               Standard 
Effect    TRTA1    Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper 
 
TRTA1     R          6.5721     0.09348      14      70.30      <.0001       0.1      6.4074      6.7367 
TRTA1     T          6.4918     0.09348      14      69.44      <.0001       0.1      6.3271      6.6564 
 
 
                                        Differences of Least Squares Means 
  
                                         Standard 
Effect    TRTA1    _TRTA1    Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper 
 
TRTA1     T        R         -0.08030     0.05719      14      -1.40      0.1821       0.1     -0.1810     0.02042 
  
  
  
  
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.14; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-expl-anova.sas, 28JAN2020 13:02                             Page 6 of 18 
 
 
Page 70 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.3: Statistical Output of Exploratory Analysis - Tepotinib Metabolite MSC2571107A 
 
Parameter: AUC0-t (h*ng/mL) for Metabolite MSC2571107A 
 
The Mixed Procedure 
 
                  Model Information 
 
Data Set                     WORK.PKPARS               
Dependent Variable           LOGAVAL                   
Covariance Structure         Variance Components       
Estimation Method            REML                      
Residual Variance Method     Profile                   
Fixed Effects SE Method      Model-Based               
Degrees of Freedom Method    Containment               
 
 
              Class Level Information 
  
Class       Levels    Values 
 
TRTA1            2    R T                            
APERIOD          2    1 2                            
  
  
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.14; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-expl-anova.sas, 28JAN2020 13:02                             Page 7 of 18 
 
 
Page 71 of 331


 
P r o t o c o l :  M S 2 0 0 0 9 5 - 0 0 3 8  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
1 6 . 1 :  S t u d y  I n f o r m a t i o n  
1 6 . 1 . 9 :  D o c u m e n t a t i o n  o f  S t a t i s t i c a l  M e t h o d s  
1 6 . 1 . 9 . 2 :  S t a t i s t i c a l  A n a l y s i s  O u t p u t  
L i s t i n g  1 6 . 1 . 9 . 2 . 3 :  S t a t i s t i c a l  O u t p u t  o f  E x p l o r a t o r y  A n a l y s i s  -  T e p o t i n i b  M e t a b o l i t e  M S C 2 5 7 1 1 0 7 A  
 
P a r a m e t e r :  A U C 0 - t  ( h * n g / m L )  f o r  M e t a b o l i t e  M S C 2 5 7 1 1 0 7 A  
 
T h e  M i x e d  P r o c e d u r e  
 
              C l a s s  L e v e l  I n f o r m a t i o n  
  
C l a s s        L e v e l s     V a l u e s  
 
U S U B J I D          1 8   
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
T :  5  x  1 0 0  m g  T F 3 ;  R :  2  x  2 5 0  m g  T F 3  
  
S o u r c e :  A D P P  2 2 J A N 2 0 2 0  1 3 : 5 5 ;  L i s t i n g  1 6 . 2 . 5 . 1 4 ;  S D T M  p a c k a g e :  1 5 J A N 2 0 2 0  
P r o g r a m :  J : \ B I O \ J 1 9 \ N - A - P H 1 - 1 9 - 0 7 0 \ t a b l e s \ t r - e x p l - a n o v a . s a s ,  2 8 J A N 2 0 2 0  1 3 : 0 2                              P a g e  8  o f  1 8  
 
 
Pa ge 7 2 of 3 3 1
PI


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.3: Statistical Output of Exploratory Analysis - Tepotinib Metabolite MSC2571107A 
 
Parameter: AUC0-t (h*ng/mL) for Metabolite MSC2571107A 
 
The Mixed Procedure 
 
              Class Level Information 
  
Class       Levels    Values 
 
SEQUENCE         2    RT TR                          
 
 
            Dimensions 
 
Covariance Parameters             2 
Columns in X                      7 
Columns in Z                     18 
Subjects                          1 
Max Obs Per Subject              35 
 
 
          Number of Observations 
 
Number of Observations Read              35 
Number of Observations Used              35 
Number of Observations Not Used           0 
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.14; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-expl-anova.sas, 28JAN2020 13:02                             Page 9 of 18 
 
 
Page 73 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.3: Statistical Output of Exploratory Analysis - Tepotinib Metabolite MSC2571107A 
 
Parameter: AUC0-t (h*ng/mL) for Metabolite MSC2571107A 
 
The Mixed Procedure 
 
                     Iteration History 
  
Iteration    Evaluations    -2 Res Log Like       Criterion 
 
        0              1        35.34606855                 
        1              2        18.61144132      0.00000217 
        2              1        18.61139966      0.00000000 
 
 
                   Convergence criteria met.                     
 
 
Covariance Parameter Estimates 
  
Cov Parm              Estimate 
 
USUBJID(SEQUENCE)       0.1093 
Residual               0.02369 
  
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.14; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-expl-anova.sas, 28JAN2020 13:02                            Page 10 of 18 
 
 
Page 74 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.3: Statistical Output of Exploratory Analysis - Tepotinib Metabolite MSC2571107A 
 
Parameter: AUC0-t (h*ng/mL) for Metabolite MSC2571107A 
 
The Mixed Procedure 
 
           Fit Statistics 
 
-2 Res Log Likelihood            18.6 
AIC (smaller is better)          22.6 
AICC (smaller is better)         23.0 
BIC (smaller is better)          24.4 
 
 
        Type 3 Tests of Fixed Effects 
  
              Num     Den 
Effect         DF      DF    F Value    Pr > F 
 
TRTA1           1      15       2.60    0.1276 
APERIOD         1      15       4.91    0.0425 
SEQUENCE        1      16       1.38    0.2571 
 
 
  
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.14; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-expl-anova.sas, 28JAN2020 13:02                            Page 11 of 18 
 
 
Page 75 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.3: Statistical Output of Exploratory Analysis - Tepotinib Metabolite MSC2571107A 
 
Parameter: AUC0-t (h*ng/mL) for Metabolite MSC2571107A 
 
The Mixed Procedure 
 
                                          Least Squares Means 
  
                               Standard 
Effect    TRTA1    Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper 
 
TRTA1     R          6.5079     0.08596      15      75.71      <.0001       0.1      6.3572      6.6586 
TRTA1     T          6.4228     0.08683      15      73.97      <.0001       0.1      6.2706      6.5751 
 
 
                                        Differences of Least Squares Means 
  
                                         Standard 
Effect    TRTA1    _TRTA1    Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper 
 
TRTA1     T        R         -0.08507     0.05274      15      -1.61      0.1276       0.1     -0.1775    0.007396 
  
  
  
  
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.14; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-expl-anova.sas, 28JAN2020 13:02                            Page 12 of 18 
 
 
Page 76 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.3: Statistical Output of Exploratory Analysis - Tepotinib Metabolite MSC2571107A 
 
Parameter: Cmax (ng/mL) for Metabolite MSC2571107A 
 
The Mixed Procedure 
 
                  Model Information 
 
Data Set                     WORK.PKPARS               
Dependent Variable           LOGAVAL                   
Covariance Structure         Variance Components       
Estimation Method            REML                      
Residual Variance Method     Profile                   
Fixed Effects SE Method      Model-Based               
Degrees of Freedom Method    Containment               
 
 
              Class Level Information 
  
Class       Levels    Values 
 
TRTA1            2    R T                            
APERIOD          2    1 2                            
  
  
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.14; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-expl-anova.sas, 28JAN2020 13:02                            Page 13 of 18 
 
 
Page 77 of 331


 
P r o t o c o l :  M S 2 0 0 0 9 5 - 0 0 3 8  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
1 6 . 1 :  S t u d y  I n f o r m a t i o n  
1 6 . 1 . 9 :  D o c u m e n t a t i o n  o f  S t a t i s t i c a l  M e t h o d s  
1 6 . 1 . 9 . 2 :  S t a t i s t i c a l  A n a l y s i s  O u t p u t  
L i s t i n g  1 6 . 1 . 9 . 2 . 3 :  S t a t i s t i c a l  O u t p u t  o f  E x p l o r a t o r y  A n a l y s i s  -  T e p o t i n i b  M e t a b o l i t e  M S C 2 5 7 1 1 0 7 A  
 
P a r a m e t e r :  C m a x  ( n g / m L )  f o r  M e t a b o l i t e  M S C 2 5 7 1 1 0 7 A  
 
T h e  M i x e d  P r o c e d u r e  
 
              C l a s s  L e v e l  I n f o r m a t i o n  
  
C l a s s        L e v e l s     V a l u e s  
 
U S U B J I D          1 8   
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
                    
            
  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
T :  5  x  1 0 0  m g  T F 3 ;  R :  2  x  2 5 0  m g  T F 3  
  
S o u r c e :  A D P P  2 2 J A N 2 0 2 0  1 3 : 5 5 ;  L i s t i n g  1 6 . 2 . 5 . 1 4 ;  S D T M  p a c k a g e :  1 5 J A N 2 0 2 0  
P r o g r a m :  J : \ B I O \ J 1 9 \ N - A - P H 1 - 1 9 - 0 7 0 \ t a b l e s \ t r - e x p l - a n o v a . s a s ,  2 8 J A N 2 0 2 0  1 3 : 0 2                             P a g e  1 4  o f  1 8  
 
 
Pa ge 7 8 of 3 3 1
PI


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.3: Statistical Output of Exploratory Analysis - Tepotinib Metabolite MSC2571107A 
 
Parameter: Cmax (ng/mL) for Metabolite MSC2571107A 
 
The Mixed Procedure 
 
              Class Level Information 
  
Class       Levels    Values 
 
SEQUENCE         2    RT TR                          
 
 
            Dimensions 
 
Covariance Parameters             2 
Columns in X                      7 
Columns in Z                     18 
Subjects                          1 
Max Obs Per Subject              36 
 
 
          Number of Observations 
 
Number of Observations Read              36 
Number of Observations Used              36 
Number of Observations Not Used           0 
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.14; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-expl-anova.sas, 28JAN2020 13:02                            Page 15 of 18 
 
 
Page 79 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.3: Statistical Output of Exploratory Analysis - Tepotinib Metabolite MSC2571107A 
 
Parameter: Cmax (ng/mL) for Metabolite MSC2571107A 
 
The Mixed Procedure 
 
                     Iteration History 
  
Iteration    Evaluations    -2 Res Log Like       Criterion 
 
        0              1        18.54420114                 
        1              1         6.94881662      0.00000000 
 
 
                   Convergence criteria met.                     
 
 
Covariance Parameter Estimates 
  
Cov Parm              Estimate 
 
USUBJID(SEQUENCE)      0.05461 
Residual               0.02145 
 
 
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.14; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-expl-anova.sas, 28JAN2020 13:02                            Page 16 of 18 
 
 
Page 80 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.3: Statistical Output of Exploratory Analysis - Tepotinib Metabolite MSC2571107A 
 
Parameter: Cmax (ng/mL) for Metabolite MSC2571107A 
 
The Mixed Procedure 
 
           Fit Statistics 
 
-2 Res Log Likelihood             6.9 
AIC (smaller is better)          10.9 
AICC (smaller is better)         11.4 
BIC (smaller is better)          12.7 
 
 
        Type 3 Tests of Fixed Effects 
  
              Num     Den 
Effect         DF      DF    F Value    Pr > F 
 
TRTA1           1      16       0.13    0.7220 
APERIOD         1      16       5.50    0.0323 
SEQUENCE        1      16       1.69    0.2126 
 
 
  
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.14; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-expl-anova.sas, 28JAN2020 13:02                            Page 17 of 18 
 
 
Page 81 of 331


 
Protocol: MS200095-0038 
_______________________________________________________________________________________________________________________ 
16.1: Study Information 
16.1.9: Documentation of Statistical Methods 
16.1.9.2: Statistical Analysis Output 
Listing 16.1.9.2.3: Statistical Output of Exploratory Analysis - Tepotinib Metabolite MSC2571107A 
 
Parameter: Cmax (ng/mL) for Metabolite MSC2571107A 
 
The Mixed Procedure 
 
                                          Least Squares Means 
  
                               Standard 
Effect    TRTA1    Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper 
 
TRTA1     R          2.1436     0.06500      16      32.98      <.0001       0.1      2.0301      2.2571 
TRTA1     T          2.1260     0.06500      16      32.71      <.0001       0.1      2.0125      2.2394 
 
 
                                        Differences of Least Squares Means 
  
                                         Standard 
Effect    TRTA1    _TRTA1    Estimate       Error      DF    t Value    Pr > |t|     Alpha       Lower       Upper 
 
TRTA1     T        R         -0.01768     0.04881      16      -0.36      0.7220       0.1     -0.1029     0.06755 
  
  
  
  
  
  
  
  
_______________________________________________________________________________________________________________________ 
T: 5 x 100 mg TF3; R: 2 x 250 mg TF3 
  
Source: ADPP 22JAN2020 13:55; Listing 16.2.5.14; SDTM package: 15JAN2020 
Program: J:\BIO\J19\N-A-PH1-19-070\tables\tr-expl-anova.sas, 28JAN2020 13:02                            Page 18 of 18 
 
Page 82 of 331


Wi n N o nli n C or e O ut p ut 
Wi n N o nli n C or e O ut p ut - - T e p oti ni b
T e p oti ni b  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 1, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 4  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.       Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 5 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0        1 0. 7 0                            2. 4 0 8      3. 6 1 1  
      2. 0 0 0        1 4. 5 0                            8. 7 0 8      1 4. 8 7  
      3. 0 0 0        3 4. 1 0                            3 3. 0 1      8 0. 5 2  
      4. 0 0 0        4 8. 2 0                            7 4. 1 6      2 2 8. 1  
      6. 0 0 0        1 0 5. 0                            2 2 7. 4      1 0 5 1.  
      8. 0 1 7        1 1 7. 0                            4 5 1. 2      2 6 3 2.  
      1 2. 0 0        2 1 8. 0                            1 1 1 8.       9 7 1 0.  
      1 6. 0 3        2 2 2. 0                            2 0 0 6. 2. 2 1 6 e + 0 0 4  
      2 4. 0 0        2 5 7. 0                            3 9 1 4. 6. 0 9 1 e + 0 0 4  
      3 6. 0 7 *      1 9 7. 0      1 8 7. 8      9. 1 9 8      6 6 3 7. 1. 4 2 0 e + 0 0 5      1. 0 0 0  
      4 8. 0 0 *      1 4 8. 0      1 4 3. 5      4. 5 2 4      8 6 8 1. 2. 2 7 3 e + 0 0 5      1. 0 0 0  
      6 0. 0 0 *      1 1 0. 0      1 0 9. 4     0. 5 5 3 3 1. 0 2 2 e + 0 0 4 3. 0 9 9 e + 0 0 5      1. 0 0 0  
      7 2. 0 0 *      7 6. 5 0      8 3. 4 9     -6. 9 8 9 1. 1 3 3 e + 0 0 4 3. 8 2 5 e + 0 0 5      1. 0 0 0  
      9 6. 0 0 *      4 5. 9 0      4 8. 5 8     - 2. 6 8 2 1. 2 7 6 e + 0 0 4 5. 0 1 8 e + 0 0 5      1. 0 0 0 
      1 2 0. 0 *      3 0. 7 0      2 8. 2 7      2. 4 3 0 1. 3 6 7 e + 0 0 4 5. 9 9 0 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      1 5. 1 0      1 6. 4 5     -1. 3 5 0 1. 4 2 0 e + 0 0 4 6. 6 7 9 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      1 0. 2 0      9. 5 7 2     0. 6 2 7 5 1. 4 5 0 e + 0 0 4 7. 1 4 5 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 6 0  
R s q _ a dj u st e d                                              0. 9 9 5 3  
C orr _ X Y                                                  -0. 9 9 8 0  
N o _ p oi nt s _l a m b d a _ z                                        8  
L a m b d a _ z                                1/ h               0. 0 2 2 6  
L a m b d a _ z _l o w er                            h              3 6. 0 6 6 7  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 0. 7 2 3 8  
Tl a g                                      h               1. 0 5 0 0  
T m a x                                      h              2 4. 0 0 0 0  
C m a x                                  n g/ m L             2 5 7. 0 0 0 0  
Pa ge 8 3 of 3 3 1
PI
PI


C m a x _ D                             n g/ m L/ m g               0. 5 7 1 1  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L              1 0. 2 0 0 0  
A U Cl a st                             h* n g/ m L           1 4 4 9 7. 1 4 9 6  
A U C all                              h* n g/ m L           1 4 4 9 7. 1 4 9 6  
A U CI N F _ o b s                          h* n g/ m L           1 4 9 4 9. 2 6 5 0  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              3 3. 2 2 0 6  
A U C _ % E xtr a p _ o b s                           %               3. 0 2 4 3  
V z _ F _ o b s                                  L            1 3 3 4. 2 6 4 3  
Cl _ F _ o b s                                L/ h              3 0. 1 0 1 8  
A U CI N F _ pr e d                         h* n g/ m L           1 4 9 2 1. 4 5 0 1  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              3 3. 1 5 8 8  
A U C _ % E xtr a p _ pr e d                          %               2. 8 4 3 6  
V z _ F _ pr e d                                 L            1 3 3 6. 7 5 1 5  
Cl _ F _ pr e d                               L/ h              3 0. 1 5 7 9  
A U M Cl a st                          h* h* n g/ m L          7 1 4 4 7 4. 9 3 7 1  
A U M CI N F _ o b s                       h* h* n g/ m L          8 1 0 4 7 0. 3 7 6 3  
A U M C _ % E xtr a p _ o b s                          %              1 1. 8 4 4 4  
A U M CI N F _ pr e d                      h* h* n g/ m L          8 0 4 5 6 4. 5 6 4 4  
A U M C _ % E xtr a p _ pr e d                         %              1 1. 1 9 7 3  
M R Tl a st                                   h              4 9. 2 8 3 8  
M R TI N F _ o b s                                h              5 4. 2 1 4 7  
M R TI N F _ pr e d                               h              5 3. 9 2 0 0  
A U C 0 _ 2 4                             h* n g/ m L            3 9 1 3. 7 6 5 8  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 2, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 4  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0        5. 8 6 0                           0. 7 3 2 5     0. 5 4 9 4  
      1. 0 0 0        1 2. 5 0                            3. 0 2 8      2. 6 6 1  
      1. 5 0 0        2 4. 7 0                            1 2. 3 3      1 5. 0 5  
      2. 0 0 0        3 8. 6 0                            2 8. 1 5      4 3. 6 1  
      3. 0 0 0        7 6. 1 0                            8 5. 5 0      1 9 6. 4  
      4. 0 0 0        9 5. 6 0                            1 7 1. 4      5 0 1. 7  
      6. 0 0 0        2 5 6. 0                            5 2 3. 0      2 4 2 0.  
      8. 0 0 0        2 2 8. 0                            1 0 0 6.      5 7 9 5.  
      1 2. 0 0        2 3 1. 0                            1 9 2 4. 1. 4 9 9 e + 0 0 4  
      1 6. 0 0        2 2 5. 0                            2 8 3 6. 2. 7 7 5 e + 0 0 4  
      2 4. 0 2        2 3 9. 0                            4 6 9 6. 6. 5 1 8 e + 0 0 4  
      3 6. 0 0        2 4 0. 0                            7 5 6 6. 1. 5 1 3 e + 0 0 5  
      4 8. 0 0        2 3 2. 0                       1. 0 4 0 e + 0 0 4 2. 7 0 2 e + 0 0 5  
      6 0. 0 0        2 4 9. 0                       1. 3 2 8 e + 0 0 4 4. 2 6 6 e + 0 0 5  
      7 2. 0 0        1 9 9. 0                       1. 5 9 6 e + 0 0 4 6. 0 2 7 e + 0 0 5  
Pa ge 8 4 of 3 3 1
PI
PI


      9 6. 0 0        1 3 7. 0                       1. 9 9 5 e + 0 0 4 9. 3 4 5 e + 0 0 5  
      1 2 0. 0 *      7 6. 3 0      7 5. 8 3     0. 4 6 9 5 2. 2 4 4 e + 0 0 4 1. 2 0 0 e + 0 0 6      1. 0 0 0  
      1 4 4. 0 *      4 7. 2 0      4 7. 7 9    -0. 5 8 6 3 2. 3 8 9 e + 0 0 4 1. 3 9 1 e + 0 0 6      1. 0 0 0  
      1 6 8. 0 *      3 0. 3 0      3 0. 1 1     0. 1 8 6 4 2. 4 8 0 e + 0 0 4 1. 5 3 3 e + 0 0 6      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 9 5  
R s q _ a dj u st e d                                              0. 9 9 8 9  
C orr _ X Y                                                  -0. 9 9 9 7  
N o _ p oi nt s _l a m b d a _ z                                        3  
L a m b d a _ z                                1/ h               0. 0 1 9 2  
L a m b d a _ z _l o w er                            h             1 2 0. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 6. 0 2 6 2  
Tl a g                                      h               0. 5 0 0 0  
T m a x                                      h               6. 0 0 0 0  
C m a x                                  n g/ m L             2 5 6. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 5 6 8 9  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L              3 0. 3 0 0 0  
A U Cl a st                             h* n g/ m L           2 4 8 0 4. 7 4 8 0  
A U C all                              h* n g/ m L           2 4 8 0 4. 7 4 8 0  
A U CI N F _ o b s                          h* n g/ m L           2 6 3 7 9. 5 8 3 2  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              5 8. 6 2 1 3  
A U C _ % E xtr a p _ o b s                           %               5. 9 6 9 9  
V z _ F _ o b s                                  L             8 8 6. 6 1 9 1  
Cl _ F _ o b s                                L/ h              1 7. 0 5 8 6  
A U CI N F _ pr e d                         h* n g/ m L           2 6 3 6 9. 8 9 3 0  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              5 8. 5 9 9 8  
A U C _ % E xtr a p _ pr e d                          %               5. 9 3 5 3  
V z _ F _ pr e d                                 L             8 8 6. 9 4 4 9  
Cl _ F _ pr e d                               L/ h              1 7. 0 6 4 9  
A U M Cl a st                          h* h* n g/ m L         1 5 3 2 9 5 3. 4 2 6 5  
A U M CI N F _ o b s                       h* h* n g/ m L         1 8 7 9 3 7 7. 4 1 0 3  
A U M C _ % E xtr a p _ o b s                          %              1 8. 4 3 2 9  
A U M CI N F _ pr e d                      h* h* n g/ m L         1 8 7 7 2 4 5. 8 1 6 5  
A U M C _ % E xtr a p _ pr e d                         %              1 8. 3 4 0 3  
M R Tl a st                                   h              6 1. 8 0 0 8  
M R TI N F _ o b s                                h              7 1. 2 4 3 6  
M R TI N F _ pr e d                               h              7 1. 1 8 9 0  
A U C 0 _ 2 4                             h* n g/ m L            4 6 9 2. 2 4 3 0  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 2, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 2  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v a ti o n s:   2 2 
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
Pa ge 8 5 of 3 3 1
PI
PI


------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0        7. 7 9 0                           0. 9 7 3 8     0. 4 8 6 9  
     0. 7 5 0 0        1 6. 9 0                            4. 0 6 0      2. 5 5 8  
      1. 0 0 0        3 2. 9 0                            1 0. 2 9      8. 2 5 5  
      1. 5 0 0        6 9. 2 0                            3 5. 8 1      4 2. 4 3  
      2. 0 0 0        9 6. 0 0                            7 7. 1 1      1 1 6. 4  
      3. 0 0 0        1 2 0. 0                            1 8 5. 1      3 9 2. 4  
      4. 0 0 0        1 4 2. 0                            3 1 6. 1      8 5 6. 4  
      6. 0 0 0        1 7 2. 0                            6 3 0. 1      2 4 5 6.  
      8. 0 0 0        1 9 2. 0                            9 9 4. 1      5 0 2 4.  
      1 2. 0 0        2 0 6. 0                            1 7 9 0. 1. 3 0 4 e + 0 0 4  
      1 6. 0 0        1 9 7. 0                            2 5 9 6. 2. 4 3 1 e + 0 0 4  
      2 4. 0 0        2 3 0. 0                            4 3 0 4. 5. 9 0 0 e + 0 0 4  
      3 6. 0 0        2 7 8. 0                            7 3 5 2. 1. 5 2 2 e + 0 0 5  
      4 8. 0 0        2 3 2. 0                       1. 0 4 0 e + 0 0 4 2. 7 9 8 e + 0 0 5  
      6 0. 0 0 *      2 1 5. 0      2 2 2. 4     -7. 4 3 9 1. 3 0 8 e + 0 0 4 4. 2 4 3 e + 0 0 5      1. 0 0 0  
      7 2. 0 2 *      1 7 9. 0      1 7 9. 5    -0. 4 7 4 4 1. 5 4 5 e + 0 0 4 5. 7 9 7 e + 0 0 5      1. 0 0 0  
      9 6. 0 0 *      1 1 5. 0      1 1 6. 9     -1. 9 4 2 1. 8 9 1 e + 0 0 4 8. 6 8 1 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      8 7. 7 0      7 6. 1 8      1 1. 5 2 2. 1 3 3 e + 0 0 4 1. 1 2 8 e + 0 0 6      1. 0 0 0  
      1 4 4. 1 *      4 6. 3 0      4 9. 5 6     -3. 2 6 1 2. 2 8 9 e + 0 0 4 1. 3 3 2 e + 0 0 6      1. 0 0 0  
      1 6 8. 0 *      3 1. 7 0      3 2. 3 2    -0. 6 2 1 7 2. 3 8 1 e + 0 0 4 1. 4 7 5 e + 0 0 6      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 0 7  
R s q _ a dj u st e d                                              0. 9 8 8 3  
C orr _ X Y                                                  -0. 9 9 5 3  
N o _ p oi nt s _l a m b d a _ z                                        6  
L a m b d a _ z                                1/ h               0. 0 1 7 9  
L a m b d a _ z _l o w er                            h              6 0. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 8. 8 0 9 3  
Tl a g                                      h               0. 2 5 0 0  
T m a x                                      h              3 6. 0 0 0 0  
C m a x                                  n g/ m L             2 7 8. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 6 1 7 8  
Tl a st                                      h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L              3 1. 7 0 0 0  
A U Cl a st                             h* n g/ m L           2 3 8 1 3. 9 8 8 4  
A U C all                              h* n g/ m L           2 3 8 1 3. 9 8 8 4  
A U CI N F _ o b s                          h* n g/ m L           2 5 5 8 8. 8 7 0 3  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              5 6. 8 6 4 2  
A U C _ % E xtr a p _ o b s                           %               6. 9 3 6 1  
V z _ F _ o b s                                  L             9 8 4. 6 2 6 7  
Cl _ F _ o b s                                L/ h              1 7. 5 8 5 8  
A U CI N F _ pr e d                         h* n g/ m L           2 5 6 2 3. 6 7 6 9  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              5 6. 9 4 1 5  
A U C _ % E xtr a p _ pr e d                          %               7. 0 6 2 6  
V z _ F _ pr e d                                 L             9 8 3. 2 8 9 2  
Cl _ F _ pr e d                               L/ h              1 7. 5 6 1 9  
A U M Cl a st                          h* h* n g/ m L         1 4 7 5 0 9 2. 5 3 3 4  
A U M CI N F _ o b s                       h* h* n g/ m L         1 8 7 2 6 4 8. 2 6 6 4  
A U M C _ % E xtr a p _ o b s                          %              2 1. 2 2 9 6  
A U M CI N F _ pr e d                      h* h* n g/ m L         1 8 8 0 4 4 4. 6 1 0 4  
A U M C _ % E xtr a p _ pr e d                         %              2 1. 5 5 6 2  
M R Tl a st                                    h              6 1. 9 4 2 3  
M R TI N F _ o b s                                h              7 3. 1 8 2 1  
M R TI N F _ pr e d                               h              7 3. 3 8 7 0  
A U C 0 _ 2 4                             h* n g/ m L            4 3 0 3. 9 7 6 0  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 2, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
Pa ge 8 6 of 3 3 1
PI


 
                                                  Date:    
 
                                                  Time:     09:23:24 
 
 
                  WINNONLIN NONCOMPARTMENTAL ANALYSIS PROGRAM 
                                   7.0.0.2535 
                            Core Version 04Jun2007 
 
Settings 
-------- 
Model:  Plasma Data, Extravascular Administration 
Number of nonmissing observations:   22 
Dose time:      0.00 
Dose amount:      450.00 
Calculation method:  Linear Trapezoidal Rule for for Increasing Values, 
                     Log Trapezoidal Rule for Decreasing Values 
Weighting for lambda_z calculations:  Uniform weighting 
Lambda_z method:  Find best fit for lambda_z,  Log regression 
 
 
Summary Table 
------------- 
      Time         Conc.      Pred.    Residual      AUC       AUMC      Weight 
          h       ng/mL       ng/mL       ng/mL     h*ng/mL   h*h*ng/mL 
------------------------------------------------------------------------------- 
     0.0000       0.0000                           0.0000     0.0000 
     0.2500       0.0000                           0.0000     0.0000 
     0.5000       0.0000                           0.0000     0.0000 
     0.7500       0.0000                           0.0000     0.0000 
      1.000        6.440                           0.8050     0.8050 
      1.500        16.70                            6.590      8.678 
      2.000        48.00                            22.77      38.94 
      3.000        74.00                            83.77      197.9 
      4.000        109.0                            175.3      526.9 
      6.000        172.0                            456.3      1995. 
      8.000        219.0                            847.3      4779. 
      12.00        294.0                            1873. 1.534e+004 
      16.00        272.0                            3005. 3.115e+004 
      24.00        283.0                            5225. 7.573e+004 
      36.03 *      230.0      232.3     -2.266      8300. 1.674e+005      1.000 
      48.00 *      167.0      170.8     -3.796 1.066e+004 2.656e+005      1.000 
      60.00 *      131.0      125.5      5.514 1.243e+004 3.613e+005      1.000 
      72.00 *      97.40      92.20      5.203 1.380e+004 4.507e+005      1.000 
      96.00 *      48.00      49.77     -1.768 1.547e+004 5.890e+005      1.000 
      120.0 *      25.70      26.87     -1.165 1.633e+004 6.805e+005      1.000 
      144.0 *      13.80      14.50    -0.7021 1.679e+004 7.406e+005      1.000 
      168.0 *      8.350      7.828     0.5217 1.705e+004 7.809e+005      1.000 
 
 
*) Starred values were included in the estimation of Lambda_z. 
 
 
Final Parameters 
--------------- 
Rsq                                                       0.9985 
Rsq_adjusted                                              0.9983 
Corr_XY                                                  -0.9993 
No_points_lambda_z                                        8 
Lambda_z                                1/h               0.0257 
Lambda_z_lower                            h              36.0333 
Lambda_z_upper                            h             168.0000 
HL_Lambda_z                               h              26.9819 
Tlag                                      h               0.7500 
Tmax                                      h              12.0000 
Cmax                                  ng/mL             294.0000 
Cmax_D                             ng/mL/mg               0.6533 
Tlast                                     h             168.0000 
Clast                                 ng/mL               8.3500 
AUClast                             h*ng/mL           17047.0867 
AUCall                              h*ng/mL           17047.0867 
AUCINF_obs                          h*ng/mL           17372.1241 
AUCINF_D_obs                     h*ng/mL/mg              38.6047 
Page 87 of 331
PI


A U C _ % E xtr a p _ o b s                           %               1. 8 7 1 0  
V z _ F _ o b s                                  L            1 0 0 8. 3 3 8 8  
Cl _ F _ o b s                                L/ h              2 5. 9 0 3 6  
A U CI N F _ pr e d                         h* n g/ m L           1 7 3 5 1. 8 1 6 2  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              3 8. 5 5 9 6  
A U C _ % E xtr a p _ pr e d                          %               1. 7 5 6 2  
V z _ F _ pr e d                                 L            1 0 0 9. 5 1 8 9  
Cl _ F _ pr e d                               L/ h              2 5. 9 3 3 9  
A U M Cl a st                          h* h* n g/ m L          7 8 0 9 1 4. 2 2 4 7  
A U M CI N F _ o b s                       h* h* n g/ m L          8 4 8 1 7 3. 1 2 5 2  
A U M C _ % E xtr a p _ o b s                          %               7. 9 2 9 9  
A U M CI N F _ pr e d                      h* h* n g/ m L          8 4 3 9 7 0. 8 7 1 2  
A U M C _ % E xtr a p _ pr e d                         %               7. 4 7 1 4  
M R Tl a st                                   h              4 5. 8 0 9 2  
M R TI N F _ o b s                                h              4 8. 8 2 3 8  
M R TI N F _ pr e d                               h              4 8. 6 3 8 8  
A U C 0 _ 2 4                             h* n g/ m L            5 2 2 4. 6 9 4 7  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 1, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 2  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0        1 6. 3 0                            2. 0 3 8      2. 0 3 8  
      1. 5 0 0        7 0. 3 0                            2 3. 6 9      3 2. 4 8  
      2. 0 0 0        1 3 5. 0                            7 5. 0 1      1 2 6. 3  
      3. 0 0 0        2 1 0. 0                            2 4 7. 5      5 7 6. 3  
      4. 0 0 0        2 6 3. 0                            4 8 4. 0      1 4 1 7.  
      6. 0 0 0        2 7 3. 0                            1 0 2 0.      4 1 0 7.  
      8. 0 0 0        2 8 0. 0                            1 5 7 3.      7 9 8 5.  
      1 2. 0 0        2 2 7. 0                            2 5 8 3. 1. 8 0 2 e + 0 0 4  
      1 6. 0 0        1 9 6. 0                            3 4 2 8. 2. 9 8 0 e + 0 0 4  
      2 4. 0 2 *      2 1 1. 0      2 0 5. 9      5. 0 6 1      5 0 5 9. 6. 2 6 8 e + 0 0 4      1. 0 0 0  
      3 6. 0 0 *      1 7 4. 0      1 7 0. 7      3. 3 3 7      7 3 5 9. 1. 3 1 2 e + 0 0 5      1. 0 0 0  
      48. 0 0 *      1 2 9. 0      1 4 1. 4     -1 2. 3 9      9 1 6 3. 2. 0 6 5 e + 0 0 5      1. 0 0 0  
      6 0. 0 0 *      1 1 6. 0      1 1 7. 1     -1. 1 4 3 1. 0 6 3 e + 0 0 4 2. 8 5 6 e + 0 0 5      1. 0 0 0  
      7 2. 0 2 *      9 6. 0 0      9 7. 0 3     -1. 0 2 6 1. 1 9 0 e + 0 0 4 3. 6 9 2 e + 0 0 5      1. 0 0 0  
      9 6. 0 0 *      6 8. 8 0      6 6. 6 2      2. 1 8 4 1. 3 8 6 e + 0 0 4 5. 3 2 4 e + 0 0 5      1. 0 0 0  
      1 2 0. 3 *      5 1. 5 0      4 5. 5 2      5. 9 7 8 1. 5 3 1 e + 0 0 4 6. 8 8 5 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      2 9. 9 0      3 1. 4 0     -1. 5 0 2 1. 6 2 5 e + 0 0 4 8. 1 1 8 e + 0 0 5      1. 0 0 0  
      1 6 8. 1 *      2 0. 7 0      2 1. 5 0    -0. 8 0 3 6 1. 6 8 6 e + 0 0 4 9. 0 5 6 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
Pa ge 8 8 of 3 3 1
PI
PI


 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 4 0  
R s q _ a dj u st e d                                              0. 9 9 3 1  
C orr _ X Y                                                  -0. 9 9 7 0  
N o _ p oi nt s _l a m b d a _ z                                        9  
L a m b d a _ z                                1/ h               0. 0 1 5 7  
L a m b d a _ z _l o w er                            h              2 4. 0 1 6 7  
L a m b d a _ z _ u p p er                            h             1 6 8. 1 1 6 7  
H L _ L a m b d a _ z                               h              4 4. 2 0 8 3  
Tl a g                                      h               0. 7 5 0 0  
T m a x                                      h               8. 0 0 0 0  
C m a x                                  n g/ m L             2 8 0. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 6 2 2 2  
Tl a st                                     h             1 6 8. 1 1 6 7  
Cl a st                                 n g/ m L              2 0. 7 0 0 0  
A U Cl a st                             h* n g/ m L           1 6 8 5 5. 7 2 2 6  
A U C all                              h* n g/ m L           1 6 8 5 5. 7 2 2 6  
A U CI N F _ o b s                          h* n g/ m L           1 8 1 7 5. 9 5 1 0  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              4 0. 3 9 1 0  
A U C _ % E xtr a p _ o b s                           %               7. 2 6 3 6  
V z _ F _ o b s                                  L            1 5 7 9. 0 4 3 5  
Cl _ F _ o b s                                L/ h              2 4. 7 5 8 0  
A U CI N F _ pr e d                         h* n g/ m L           1 8 2 2 7. 2 0 5 9  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              4 0. 5 0 4 9  
A U C _ % E xtr a p _ pr e d                          %               7. 5 2 4 4  
V z _ F _ pr e d                                 L            1 5 7 4. 6 0 3 2  
Cl _ F _ pr e d                               L/ h              2 4. 6 8 8 4  
A U M Cl a st                          h* h* n g/ m L          9 0 5 5 8 9. 6 9 8 1  
A U M CI N F _ o b s                       h* h* n g/ m L         1 2 1 1 7 4 5. 1 4 1 5  
A U M C _ % E xtr a p _ o b s                          %              2 5. 2 6 5 7  
A U M CI N F _ pr e d                      h* h* n g/ m L         1 2 2 3 6 3 0. 9 3 9 9  
A U M C _ % E xtr a p _ pr e d                         %              2 5. 9 9 1 6  
M R Tl a st                                   h              5 3. 7 2 5 9  
M R TI N F _ o b s                                h              6 6. 6 6 7 5  
M R TI N F _ pr e d                               h              6 7. 1 3 2 1  
A U C 0 _ 2 4                             h* n g/ m L            5 0 5 5. 6 6 6 6  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 1, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 3  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                            0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
Pa ge 8 9 of 3 3 1
PI
PI


     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0        2 1. 4 0                            5. 3 5 0      8. 0 2 5  
      2. 0 0 0        1 6. 7 0                            1 4. 8 3      2 4. 5 1  
      3. 0 0 0        5 2. 6 0                            4 9. 4 8      1 2 0. 1  
      4. 0 0 0        5 3. 3 0                            1 0 2. 4      3 0 5. 6  
      6. 0 0 0        1 0 0. 0                            2 5 5. 7      1 1 1 9.  
      8. 0 0 0        1 0 7. 0                            4 6 2. 7      2 5 7 5.  
      1 2. 0 0        1 7 0. 0                            1 0 1 7.      8 3 6 7.  
      1 6. 0 0        1 7 5. 0                            1 7 0 7. 1. 8 0 5 e + 0 0 4  
      2 4. 0 0        1 7 3. 0                            3 0 9 9. 4. 5 8 8 e + 0 0 4  
      3 6. 0 0        2 0 8. 0                            5 3 8 5. 1. 1 5 7 e + 0 0 5  
      4 8. 0 0        1 3 6. 0                            7 4 1 8. 2. 0 0 3 e + 0 0 5  
      6 0. 0 3        1 0 3. 0                            8 8 4 7. 2. 7 7 0 e + 0 0 5  
      7 2. 0 0        7 0. 1 0                            9 8 7 0. 3. 4 4 2 e + 0 0 5  
      9 6. 0 0 *      3 2. 8 0      3 1. 7 7      1. 0 2 9 1. 1 0 5 e + 0 0 4 4. 4 1 4 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      1 7. 2 0      1 8. 2 8     -1. 0 8 1 1. 1 6 3 e + 0 0 4 5. 0 3 3 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      1 0. 8 0      1 0. 5 2     0. 2 8 0 5 1. 1 9 6 e + 0 0 4 5. 4 6 6 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      6. 0 7 0      6. 0 5 3    0. 0 1 6 8 7 1. 2 1 6 e + 0 0 4 5. 7 7 1 e + 0 0 5      1. 0 0 0 
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 6 5  
R s q _ a dj u st e d                                              0. 9 9 4 7  
C orr _ X Y                                                  -0. 9 9 8 2  
N o _ p oi nt s _l a m b d a _ z                                        4  
L a m b d a _ z                                1/ h               0. 0 2 3 0  
L a m b d a _ z _l o w er                            h              9 6. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 0. 1 0 1 0  
Tl a g                                      h               1. 0 0 0 0  
T m a x                                      h              3 6. 0 0 0 0  
C m a x                                  n g/ m L             2 0 8. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 4 6 2 2  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L               6. 0 7 0 0  
A U Cl a st                             h* n g/ m L           1 2 1 5 5. 8 9 1 7  
A U C all                              h* n g/ m L           1 2 1 5 5. 8 9 1 7  
A U CI N F _ o b s                          h* n g/ m L           1 2 4 1 9. 4 9 0 9  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              2 7. 5 9 8 9  
A U C _ % E xtr a p _ o b s                           %               2. 1 2 2 5  
V z _ F _ o b s                                  L            1 5 7 3. 4 9 0 2  
Cl _ F _ o b s                                L/ h              3 6. 2 3 3 4  
A U CI N F _ pr e d                         h* n g/ m L           1 2 4 1 8. 7 5 8 1  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              2 7. 5 9 7 2  
A U C _ % E xtr a p _ pr e d                          %               2. 1 1 6 7  
V z _ F _ pr e d                                 L            1 5 7 3. 5 8 3 1  
Cl _ F _ pr e d                               L/ h              3 6. 2 3 5 5  
A U M Cl a st                          h* h* n g/ m L          5 7 7 0 9 7. 4 8 4 1  
A U M CI N F _ o b s                       h* h* n g/ m L          6 3 2 8 2 9. 3 4 5 4  
A U M C _ % E xtr a p _ o b s                          %               8. 8 0 6 8  
A U M CI N F _ pr e d                      h* h* n g/ m L          6 3 2 6 7 4. 4 0 9 6  
A U M C _ % E xtr a p _ pr e d                         %               8. 7 8 4 4  
M R Tl a st                                   h              4 7. 4 7 4 7  
M R TI N F _ o b s                                h              5 0. 9 5 4 5  
M R TI N F _ pr e d                               h              5 0. 9 4 5 1  
A U C 0 _ 2 4                             h* n g/ m L            3 0 9 8. 7 1 1 2  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 1, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 3  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
Pa ge 9 0 of 3 3 1
PI
PI


                            Core Version 04Jun2007 
 
Settings 
-------- 
Model:  Plasma Data, Extravascular Administration 
Number of nonmissing observations:   22 
Dose time:      0.00 
Dose amount:      450.00 
Calculation method:  Linear Trapezoidal Rule for for Increasing Values, 
                     Log Trapezoidal Rule for Decreasing Values 
Weighting for lambda_z calculations:  Uniform weighting 
Lambda_z method:  Find best fit for lambda_z,  Log regression 
 
 
Summary Table 
------------- 
      Time         Conc.      Pred.    Residual      AUC       AUMC      Weight 
          h       ng/mL       ng/mL       ng/mL     h*ng/mL   h*h*ng/mL 
------------------------------------------------------------------------------- 
     0.0000       0.0000                           0.0000     0.0000 
     0.2500       0.0000                           0.0000     0.0000 
     0.5000       0.0000                           0.0000     0.0000 
     0.7833       0.0000                           0.0000     0.0000 
      1.000       0.0000                           0.0000     0.0000 
      1.500        11.50                            2.875      4.313 
      2.000        22.80                            11.45      20.03 
      3.000        92.10                            68.90      181.0 
      4.000        177.0                            203.5      673.1 
      6.000        276.0                            656.5      3037. 
      8.000        245.0                            1177.      6669. 
      12.00        246.0                            2159. 1.649e+004 
      16.00        219.0                            3088. 2.946e+004 
      24.00        201.0                            4767. 6.295e+004 
      36.00        188.0                            7100. 1.328e+005 
      48.00        152.0                            9132. 2.177e+005 
      60.00        153.0                       1.096e+004 3.166e+005 
      72.00 *      136.0      138.5     -2.508 1.269e+004 4.307e+005      1.000 
      96.00 *      89.30      87.65      1.648 1.536e+004 6.523e+005      1.000 
      120.0 *      55.40      55.47   -0.06869 1.706e+004 8.347e+005      1.000 
      144.0 *      35.80      35.10     0.6978 1.814e+004 9.760e+005      1.000 
      168.0 *      21.80      22.21    -0.4137 1.882e+004 1.081e+006      1.000 
 
 
*) Starred values were included in the estimation of Lambda_z. 
 
 
Final Parameters 
--------------- 
Rsq                                                       0.9993 
Rsq_adjusted                                              0.9991 
Corr_XY                                                  -0.9997 
No_points_lambda_z                                        5 
Lambda_z                                1/h               0.0191 
Lambda_z_lower                            h              72.0000 
Lambda_z_upper                            h             168.0000 
HL_Lambda_z                               h              36.3575 
Tlag                                      h               1.0000 
Tmax                                      h               6.0000 
Cmax                                  ng/mL             276.0000 
Cmax_D                             ng/mL/mg               0.6133 
Tlast                                     h             168.0000 
Clast                                 ng/mL              21.8000 
AUClast                             h*ng/mL           18817.5271 
AUCall                              h*ng/mL           18817.5271 
AUCINF_obs                          h*ng/mL           19960.9979 
AUCINF_D_obs                     h*ng/mL/mg              44.3578 
AUC_%Extrap_obs                           %               5.7285 
Vz_F_obs                                  L            1182.4937 
Cl_F_obs                                L/h              22.5440 
AUCINF_pred                         h*ng/mL           19982.6986 
AUCINF_D_pred                    h*ng/mL/mg              44.4060 
AUC_%Extrap_pred                          %               5.8309 
Vz_F_pred                                 L            1181.2095 
Page 91 of 331


Cl _ F _ pr e d                               L/ h              2 2. 5 1 9 5  
A U M Cl a st                          h* h* n g/ m L         1 0 8 0 9 5 0. 4 8 9 7  
A U M CI N F _ o b s                       h* h* n g/ m L         1 3 3 3 0 3 1. 7 9 8 7  
A U M C _ % E xtr a p _ o b s                          %              1 8. 9 1 0 4  
A U M CI N F _ pr e d                      h* h* n g/ m L         1 3 3 7 8 1 5. 7 8 4 1  
A U M C _ % E xtr a p _ pr e d                         %              1 9. 2 0 0 3  
M R Tl a st                                   h              5 7. 4 4 3 8  
M R TI N F _ o b s                                h              6 6. 7 8 1 8  
M R TI N F _ pr e d                               h              6 6. 9 4 8 7  
A U C 0 _ 2 4                             h* n g/ m L            4 7 6 6. 7 5 9 4  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 2, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 1  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 1 6 7       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0        6. 0 5 0                           0. 7 0 5 8     0. 5 2 9 4  
      1. 0 0 0        7. 9 9 0                            2. 4 6 1      2. 0 9 5  
      1. 5 0 0        1 8. 4 0                            9. 0 5 8      1 0. 9 9  
      2. 0 0 0        8 9. 2 0                            3 5. 9 6      6 2. 4 9  
      3. 0 0 0        7 6. 8 0                            1 1 8. 8      2 6 8. 6  
      4. 0 0 0        1 2 2. 0                            2 1 8. 2      6 2 7. 8  
      6. 0 0 0        2 4 9. 0                            5 8 9. 2      2 6 1 0.  
      8. 0 0 0        3 0 4. 0                            1 1 4 2.      6 5 3 6.  
      1 2. 0 0        3 5 1. 0                            2 4 5 2. 1. 9 8 2 e + 0 0 4  
      1 6. 0 0        3 0 9. 0                            3 7 7 0. 3. 8 2 2 e + 0 0 4  
      2 4. 0 0        2 5 5. 0                            6 0 2 0. 8. 2 9 2 e + 0 0 4  
      3 6. 0 0        1 9 3. 0                            8 6 9 0. 1. 6 2 3 e + 0 0 5  
      4 8. 0 0        1 6 2. 0                       1. 0 8 1 e + 0 0 4 2. 5 1 2 e + 0 0 5  
      6 0. 0 0        1 2 2. 0                       1. 2 5 1 e + 0 0 4 3. 4 2 1 e + 0 0 5  
      7 2. 0 0        7 5. 5 0                       1. 3 6 7 e + 0 0 4 4. 1 8 3 e + 0 0 5  
      9 6. 0 0        5 9. 0 0                       1. 5 2 8 e + 0 0 4 5. 5 2 4 e + 0 0 5  
      1 2 0. 0 *      3 0. 1 0      2 9. 7 4     0. 3 6 0 5 1. 6 3 1 e + 0 0 4 6. 6 2 3 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      1 6. 9 0      1 7. 3 1    -0. 4 1 2 2 1. 6 8 6 e + 0 0 4 7. 3 4 1 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      1 0. 2 0      1 0. 0 8     0. 1 2 2 1 1. 7 1 7 e + 0 0 4 7. 8 3 5 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 8 5  
R s q _ a dj u st e d                                              0. 9 9 7 0  
C orr _ X Y                                                  -0. 9 9 9 3  
Pa ge 9 2 of 3 3 1
PI
PI


N o _ p oi nt s _l a m b d a _ z                                        3 
L a m b d a _ z                                1/ h               0. 0 2 2 5  
L a m b d a _ z _l o w er                            h             1 2 0. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 0. 7 4 5 7  
Tl a g                                      h               0. 5 1 6 7  
T m a x                                      h              1 2. 0 0 0 0  
C m a x                                  n g/ m L             3 5 1. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 7 8 0 0  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L              1 0. 2 0 0 0  
A U Cl a st                             h* n g/ m L           1 7 1 7 4. 0 4 6 7  
A U C all                              h* n g/ m L           1 7 1 7 4. 0 4 6 7  
A U CI N F _ o b s                          h* n g/ m L           1 7 6 2 6. 4 8 4 6  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              3 9. 1 7 0 0  
A U C _ % E xtr a p _ o b s                           %               2. 5 6 6 8  
V z _ F _ o b s                                  L            1 1 3 2. 4 1 5 0  
Cl _ F _ o b s                                L/ h              2 5. 5 2 9 8  
A U CI N F _ pr e d                         h* n g/ m L           1 7 6 2 1. 0 6 6 5  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              3 9. 1 5 7 9  
A U C _ % E xtr a p _ pr e d                          %               2. 5 3 6 8  
V z _ F _ pr e d                                 L            1 1 3 2. 7 6 3 2  
Cl _ F _ pr e d                               L/ h              2 5. 5 3 7 6  
A U M Cl a st                          h* h* n g/ m L          7 8 3 4 7 4. 7 9 4 2 
A U M CI N F _ o b s                       h* h* n g/ m L          8 7 9 5 5 2. 9 9 5 0  
A U M C _ % E xtr a p _ o b s                          %              1 0. 9 2 3 5  
A U M CI N F _ pr e d                      h* h* n g/ m L          8 7 8 4 0 2. 4 2 7 2  
A U M C _ % E xtr a p _ pr e d                         %              1 0. 8 0 6 9  
M R Tl a st                                   h              4 5. 6 1 9 7  
M R TI N F _ o b s                                h              4 9. 8 9 9 5  
M R TI N F _ pr e d                               h              4 9. 8 4 9 6  
A U C 0 _ 2 4                             h* n g/ m L            6 0 1 9. 5 0 9 4  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 1, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 4  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:   Pl a s m a D at a,  E xtr a v a s c ul ar  A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 6 6 7       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0        7. 3 8 0                           0. 9 2 2 5     0. 6 9 1 9  
      1. 0 0 0        9. 9 0 0                            3. 0 8 3      2. 6 2 1  
      1. 5 0 0        2 6. 4 0                            1 2. 1 6      1 5. 0 0  
      2. 0 0 0        5 1. 4 0                            3 1. 6 1      5 0. 6 0  
      3. 0 0 0        9 5. 7 0                            1 0 5. 2      2 4 5. 5  
      4. 0 0 0        1 2 6. 0                            2 1 6. 0      6 4 1. 1  
      6. 0 0 0        1 7 4. 0                            5 1 6. 0      2 1 8 9.  
Pa ge 9 3 of 3 3 1
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PI


      8. 0 0 0        1 6 0. 0                            8 4 9. 8      4 5 2 1.  
      1 2. 0 0 *      1 5 3. 0      1 5 8. 3     -5. 3 0 2      1 4 7 6. 1. 0 7 7 e + 0 0 4      1. 0 0 0  
      1 6. 0 0 *      1 4 4. 0      1 4 5. 0     -1. 0 2 4      2 0 7 0. 1. 9 0 7 e + 0 0 4      1. 0 0 0  
      2 4. 0 0 *      1 2 0. 0      1 2 1. 7     -1. 7 1 5      3 1 2 3. 4. 0 0 1 e + 0 0 4      1. 0 0 0  
      3 6. 0 0 *      9 2. 2 0      9 3. 5 8     -1. 3 8 4      4 3 8 8. 7. 7 6 5 e + 0 0 4      1. 0 0 0  
      4 8. 0 0 *      7 7. 4 0      7 1. 9 5      5. 4 4 5      5 4 0 4. 1. 2 0 1 e + 0 0 5      1. 0 0 0  
      6 0. 0 0 *      5 3. 5 0      5 5. 3 2     -1. 8 2 4      6 1 8 0. 1. 6 1 8 e + 0 0 5      1. 0 0 0  
      7 2. 0 0 *      4 6. 3 0      4 2. 5 4      3. 7 6 2      6 7 7 8. 2. 0 1 1 e + 0 0 5      1. 0 0 0  
      9 6. 0 0 *      2 3. 8 0      2 5. 1 5     -1. 3 4 7      7 5 8 9. 2. 6 8 2 e + 0 0 5      1. 0 0 0  
      1 2 0. 2 *      1 5. 3 0      1 4. 8 2     0. 4 8 2 4      8 0 5 4. 3. 1 8 0 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      8. 6 3 0      8. 7 8 9    -0. 1 5 8 6      8 3 3 2. 3. 5 4 4 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      5. 1 3 0      5. 1 9 6   -0. 0 6 5 5 9      8 4 9 3. 3. 7 9 4 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 8 5  
R s q _ a dj u st e d                                              0. 9 9 8 4  
C orr _ X Y                                                  -0. 9 9 9 3  
N o _ p oi nt s _l a m b d a _ z                                       1 1  
L a m b d a _ z                                1/ h               0. 0 2 1 9  
L a m b d a _ z _l o w er                            h              1 2. 0 0 0 0  
L a m b d a _ z _ u p p er                            h              1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 1. 6 4 7 8  
Tl a g                                      h               0. 5 0 0 0  
T m a x                                      h               6. 0 0 0 0  
C m a x                                  n g/ m L             1 7 4. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 3 8 6 7  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L               5. 1 3 0 0  
A U Cl a st                             h* n g/ m L            8 4 9 3. 2 4 0 3  
A U C all                              h* n g/ m L            8 4 9 3. 2 4 0 3  
A U CI N F _ o b s                          h* n g/ m L            8 7 2 7. 4 6 6 7  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              1 9. 3 9 4 4  
A U C _ % E xtr a p _ o b s                           %               2. 6 8 3 8  
V z _ F _ o b s                                  L            2 3 5 4. 1 9 7 2  
Cl _ F _ o b s                                L/ h              5 1. 5 6 1 4  
A U CI N F _ pr e d                         h* n g/ m L            8 7 3 0. 4 6 1 3  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              1 9. 4 0 1 0  
A U C _ % E xtr a p _ pr e d                          %               2. 7 1 7 2  
V z _ F _ pr e d                                 L            2 3 5 3. 3 8 9 7  
Cl _ F _ pr e d                               L/ h              5 1. 5 4 3 7  
A U M Cl a st                          h* h* n g/ m L          3 7 9 4 1 3. 2 4 7 3  
A U M CI N F _ o b s                       h* h* n g/ m L          4 2 9 4 5 7. 6 3 8 2  
A U M C _ % E xtr a p _ o b s                          %              1 1. 6 5 2 9  
A U M CI N F _ pr e d                      h* h* n g/ m L          4 3 0 0 9 7. 4 5 5 2  
A U M C _ % E xtr a p _ pr e d                         %              1 1. 7 8 4 4  
M R Tl a st                                   h              4 4. 6 7 2 4  
M R TI N F _ o b s                                h              4 9. 2 0 7 6  
M R TI N F _ pr e d                               h              4 9. 2 6 4 0  
A U C 0 _ 2 4                             h* n g/ m L            3 1 2 2. 6 1 0 0  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 1, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 3  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
Pa ge 9 4 of 3 3 1
PI
PI


Dose amount:      450.00 
Calculation method:  Linear Trapezoidal Rule for for Increasing Values, 
                     Log Trapezoidal Rule for Decreasing Values 
Weighting for lambda_z calculations:  Uniform weighting 
Lambda_z method:  Find best fit for lambda_z,  Log regression 
 
 
Summary Table 
------------- 
      Time         Conc.      Pred.    Residual      AUC       AUMC      Weight 
          h       ng/mL       ng/mL       ng/mL     h*ng/mL   h*h*ng/mL 
------------------------------------------------------------------------------- 
     0.0000       0.0000                           0.0000     0.0000 
     0.2500       0.0000                           0.0000     0.0000 
     0.5000       0.0000                           0.0000     0.0000 
     0.8167       0.0000                           0.0000     0.0000 
      1.017        5.750                           0.5750     0.5846 
      1.500        25.10                            8.030      11.10 
      2.000        35.70                            23.23      38.36 
      3.000        109.0                            95.58      237.6 
      4.000        109.0                            204.6      619.1 
      6.000        138.0                            451.6      1883. 
      8.000        131.0                            720.5      3763. 
      12.00        155.0                            1293.      9579. 
      16.00        172.0                            1947. 1.880e+004 
      24.00        197.0                            3423. 4.872e+004 
      36.00        221.0                            5931. 1.248e+005 
      48.00 *      173.0      177.3     -4.268      8283. 2.230e+005      1.000 
      60.00 *      145.0      140.6      4.432 1.019e+004 3.255e+005      1.000 
      72.00 *      108.0      111.5     -3.465 1.169e+004 4.245e+005      1.000 
      96.00 *      75.20      70.09      5.111 1.387e+004 6.056e+005      1.000 
      120.0 *      41.80      44.07     -2.272 1.523e+004 7.514e+005      1.000 
      144.0 *      27.80      27.71    0.08787 1.606e+004 8.595e+005      1.000 
      168.0 *      17.50      17.43    0.07471 1.659e+004 9.423e+005      1.000 
 
 
*) Starred values were included in the estimation of Lambda_z. 
 
 
Final Parameters 
--------------- 
Rsq                                                       0.9977 
Rsq_adjusted                                              0.9973 
Corr_XY                                                  -0.9989 
No_points_lambda_z                                        7 
Lambda_z                                1/h               0.0193 
Lambda_z_lower                            h              48.0000 
Lambda_z_upper                            h             168.0000 
HL_Lambda_z                               h              35.8565 
Tlag                                      h               0.8167 
Tmax                                      h              36.0000 
Cmax                                  ng/mL             221.0000 
Cmax_D                             ng/mL/mg               0.4911 
Tlast                                     h             168.0000 
Clast                                 ng/mL              17.5000 
AUClast                             h*ng/mL           16590.5637 
AUCall                              h*ng/mL           16590.5637 
AUCINF_obs                          h*ng/mL           17495.8378 
AUCINF_D_obs                     h*ng/mL/mg              38.8796 
AUC_%Extrap_obs                           %               5.1742 
Vz_F_obs                                  L            1330.5150 
Cl_F_obs                                L/h              25.7204 
AUCINF_pred                         h*ng/mL           17491.9728 
AUCINF_D_pred                    h*ng/mL/mg              38.8711 
AUC_%Extrap_pred                          %               5.1533 
Vz_F_pred                                 L            1330.8090 
Cl_F_pred                               L/h              25.7261 
AUMClast                          h*h*ng/mL          942331.8817 
AUMCINF_obs                       h*h*ng/mL         1141247.6947 
AUMC_%Extrap_obs                          %              17.4297 
AUMCINF_pred                      h*h*ng/mL         1140398.4520 
AUMC_%Extrap_pred                         %              17.3682 
MRTlast                                   h              56.7993 
Page 95 of 331


M R TI N F _ o b s                                h              6 5. 2 2 9 7  
M R TI N F _ pr e d                               h              6 5. 1 9 5 5  
A U C 0 _ 2 4                             h* n g/ m L            3 4 2 2. 5 1 9 7  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 1, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 2  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s e r v ati o n s:   2 2 
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 3 3       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0        6. 0 6 0                            1. 4 1 4      2. 1 2 1  
      2. 0 0 0        1 3. 3 0                            6. 2 5 4      1 1. 0 4  
      3. 0 0 0        3 9. 7 0                            3 2. 7 5      8 3. 8 9  
      4. 0 0 0        4 9. 0 0                            7 7. 1 0      2 4 1. 4  
      6. 0 0 0        2 2 7. 0                            3 5 3. 1      1 7 9 9 . 
      8. 0 0 0        2 3 1. 0                            8 1 1. 1      5 0 0 9.  
      1 2. 0 0        2 4 1. 0                            1 7 5 5. 1. 4 4 9 e + 0 0 4  
      1 6. 0 0        2 0 5. 0                            2 6 4 5. 2. 6 9 0 e + 0 0 4  
      2 4. 0 0        1 9 5. 0                            4 2 4 5. 5. 8 8 4 e + 0 0 4  
      3 6. 0 0 *      1 8 1. 0      1 8 5. 7     -4. 7 0 3      6 5 0 0. 1. 2 6 3 e + 0 0 5      1. 0 0 0  
      4 8. 0 2 *      1 4 5. 0      1 4 7. 9     -2. 9 3 6      8 4 5 1. 2. 0 7 8 e + 0 0 5      1. 0 0 0  
      6 0. 0 0 *      1 2 5. 0      1 1 7. 9      7. 0 7 6 1. 0 0 7 e + 0 0 4 2. 9 4 8 e + 0 0 5      1. 0 0 0  
      7 2. 0 0 *      9 2. 5 0      9 3. 9 7     -1. 4 7 1 1. 1 3 6 e + 0 0 4 3. 7 9 9 e + 0 0 5      1. 0 0 0  
      9 6. 0 0 *      5 9. 8 0      5 9. 6 7     0. 1 2 7 1 1. 3 1 6 e + 0 0 4 5. 2 9 5 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      3 8. 0 0      3 7. 8 9     0. 1 0 6 9 1. 4 3 1 e + 0 0 4 6. 5 3 0 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      2 4. 8 0      2 4. 0 6     0. 7 3 7 4 1. 5 0 6 e + 0 0 4 7. 5 0 4 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      1 4. 8 0      1 5. 2 8    -0. 4 8 0 1 1. 5 5 2 e + 0 0 4 8. 2 2 5 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 8 8  
R s q _ a dj u st e d                                              0. 9 9 8 6  
C orr _ X Y                                                  -0. 9 9 9 4  
N o _ p oi nt s _l a m b d a _ z                                        8  
L a m b d a _ z                                1/ h               0. 0 1 8 9  
L a m b d a _ z _l o w er                            h              3 6. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 6. 6 3 3 3  
Tl a g                                      h               1. 0 3 3 3  
T m a x                                      h              1 2. 0 0 0 0  
Pa ge 9 6 of 3 3 1
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C m a x                                  n g/ m L             2 4 1. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 5 3 5 6  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L              1 4. 8 0 0 0  
A U Cl a st                             h* n g/ m L           1 5 5 2 0. 8 8 1 4  
A U C all                              h* n g/ m L           1 5 5 2 0. 8 8 1 4  
A U CI N F _ o b s                          h* n g/ m L           1 6 3 0 3. 0 7 2 2  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              3 6. 2 2 9 0  
A U C _ % E xtr a p _ o b s                           %               4. 7 9 7 8  
V z _ F _ o b s                                  L            1 4 5 8. 7 9 4 3  
Cl _ F _ o b s                                L/ h              2 7. 6 0 2 2  
A U CI N F _ pr e d                         h* n g/ m L           1 6 3 2 8. 4 4 5 0  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              3 6. 2 8 5 4  
A U C _ % E xtr a p _ pr e d                          %               4. 9 4 5 7  
V z _ F _ pr e d                                 L            1 4 5 6. 5 2 7 5  
Cl _ F _ pr e d                               L/ h              2 7. 5 5 9 3  
A U M Cl a st                          h* h* n g/ m L          8 2 2 4 5 9. 3 3 6 9  
A U M CI N F _ o b s                       h* h* n g/ m L          9 9 5 2 0 6. 7 5 3 9  
A U M C _ % E xtr a p _ o b s                          %              1 7. 3 5 7 9  
A U M CI N F _ pr e d                      h* h* n g/ m L         1 0 0 0 8 1 0. 3 6 6 0  
A U M C _ % E xtr a p _ pr e d                         %              1 7. 8 2 0 7  
M R Tl a st                                   h              5 2. 9 9 0 5  
M R TI N F _ o b s                                h              6 1. 0 4 4 1  
M R TI N F _ pr e d                               h              6 1. 2 9 2 4  
A U C 0 _ 2 4                             h* n g/ m L            4 2 4 4. 8 3 0 0  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 1, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 2  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:   Pl a s m a D at a,  E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 6 6 7        7. 9 3 0                            1. 0 5 7     0. 8 1 0 6  
      1. 0 0 0        1 0. 2 0                            3. 1 7 3      2. 7 1 0  
      1. 5 0 0        4 1. 8 0                            1 6. 1 7      2 0. 9 3  
      2. 0 0 0        6 7. 9 0                            4 3. 6 0      7 0. 5 6  
      3. 0 0 0        1 0 2. 0                            1 2 8. 5      2 9 1. 5  
      4. 0 0 0        1 3 0. 0                            2 4 4. 5      7 0 4. 5  
      6. 0 0 0        1 8 6. 0                            5 6 0. 5      2 3 4 0.  
      8. 0 1 7        2 3 4. 0                            9 8 4. 0      5 3 5 7.  
      1 2. 0 0        2 2 2. 0                            1 8 9 2. 1. 4 4 3 e + 0 0 4  
      1 6. 0 0        2 6 1. 0                            2 8 5 8. 2. 8 1 1 e + 0 0 4  
      2 4. 0 2        2 6 7. 0                            4 9 7 4. 7. 0 5 5 e + 0 0 4  
      3 6. 0 0 *      1 8 0. 0      1 7 8. 9      1. 0 9 7      7 6 1 9. 1. 4 8 9 e + 0 0 5      1. 0 0 0  
      4 8. 0 0 *      1 4 2. 0      1 3 9. 5      2. 4 9 6      9 5 4 2. 2. 2 9 2 e + 0 0 5      1. 0 0 0  
      6 0. 0 0 *      1 1 1. 0      1 0 8. 8      2. 2 1 9 1. 1 0 5 e + 0 0 4 3. 1 0 4 e + 0 0 5      1. 0 0 0  
Pa ge 9 7 of 3 3 1
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      7 2. 0 0 *      8 5. 0 0      8 4. 8 2     0. 1 7 5 3 1. 2 2 2 e + 0 0 4 3. 8 7 2 e + 0 0 5      1. 0 0 0  
      9 6. 0 0 *      4 9. 9 0      5 1. 5 8     -1. 6 7 7 1. 3 8 0 e + 0 0 4 5. 1 8 4 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      2 9. 1 0      3 1. 3 6     -2. 2 6 1 1. 4 7 3 e + 0 0 4 6. 1 7 4 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      1 9. 6 0      1 9. 0 7     0. 5 3 0 9 1. 5 3 1 e + 0 0 4 6. 9 3 1 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      1 2. 0 0      1 1. 5 9     0. 4 0 5 1 1. 5 6 8 e + 0 0 4 7. 5 0 7 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 8 6  
R s q _ a dj u st e d                                              0. 9 9 8 4  
C orr _ X Y                                                  -0. 9 9 9 3  
N o _ p oi nt s _l a m b d a _ z                                        8  
L a m b d a _ z                                1/ h               0. 0 2 0 7  
L a m b d a _ z _l o w er                            h              3 6. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 3. 4 3 7 9  
Tl a g                                      h               0. 5 0 0 0  
T m a x                                      h              2 4. 0 1 6 7  
C m a x                                  n g/ m L             2 6 7. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 5 9 3 3  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L              1 2. 0 0 0 0  
A U Cl a st                             h* n g/ m L           1 5 6 7 6. 9 2 6 5  
A U C all                              h* n g/ m L           1 5 6 7 6. 9 2 6 5  
A U CI N F _ o b s                          h* n g/ m L           1 6 2 5 5. 8 1 4 9  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              3 6. 1 2 4 0  
A U C _ % E xtr a p _ o b s                           %               3. 5 6 1 1  
V z _ F _ o b s                                  L            1 3 3 5. 4 1 8 4  
Cl _ F _ o b s                                L/ h              2 7. 6 8 2 4  
A U CI N F _ pr e d                         h* n g/ m L           1 6 2 3 6. 2 7 3 1  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              3 6. 0 8 0 6  
A U C _ % E xtr a p _ pr e d                          %               3. 4 4 5 0  
V z _ F _ pr e d                                 L            1 3 3 7. 0 2 5 7  
Cl _ F _ pr e d                               L/ h              2 7. 7 1 5 7  
A U M Cl a st                          h* h* n g/ m L          7 5 0 6 8 9. 4 7 4 4  
A U M CI N F _ o b s                       h* h* n g/ m L          8 7 5 8 6 8. 7 0 6 2  
A U M C _ % E xtr a p _ o b s                          %              1 4. 2 9 2 0  
A U M CI N F _ pr e d                      h* h* n g/ m L          8 7 1 6 4 2. 9 7 6 5  
A U M C _ % E x tr a p _ pr e d                         %              1 3. 8 7 6 5 
M R Tl a st                                   h              4 7. 8 8 5 0  
M R TI N F _ o b s                                h              5 3. 8 8 0 3  
M R TI N F _ pr e d                               h              5 3. 6 8 4 9  
A U C 0 _ 2 4                             h* n g/ m L            4 9 6 9. 9 8 7 9  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 1, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 1  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
Pa ge 9 8 of 3 3 1
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Summary Table 
------------- 
      Time         Conc.      Pred.    Residual      AUC       AUMC      Weight 
          h       ng/mL       ng/mL       ng/mL     h*ng/mL   h*h*ng/mL 
------------------------------------------------------------------------------- 
     0.0000       0.0000                           0.0000     0.0000 
     0.2500       0.0000                           0.0000     0.0000 
     0.5000       0.0000                           0.0000     0.0000 
     0.7500       0.0000                           0.0000     0.0000 
      1.050       0.0000                           0.0000     0.0000 
      1.500       0.0000                           0.0000     0.0000 
      2.017       0.0000                           0.0000     0.0000 
      3.000        18.30                            8.997      26.99 
      4.000        26.50                            31.40      107.4 
      6.000        98.60                            156.5      805.0 
      8.000        153.0                            408.1      2621. 
      12.00        226.0                            1166. 1.049e+004 
      16.00        248.0                            2114. 2.385e+004 
      24.00        266.0                            4170. 6.526e+004 
      36.00 *      245.0      239.3      5.675      7234. 1.569e+005      1.000 
      48.00 *      183.0      184.5     -1.527      9784. 2.633e+005      1.000 
      60.00 *      133.0      142.3     -9.276 1.166e+004 3.642e+005      1.000 
      72.00 *      108.0      109.7     -1.699 1.311e+004 4.590e+005      1.000 
      96.07 *      68.50      65.12      3.380 1.519e+004 6.326e+005      1.000 
      120.0 *      39.90      38.77      1.131 1.646e+004 7.680e+005      1.000 
      144.1 *      24.60      22.99      1.610 1.722e+004 8.680e+005      1.000 
      168.6 *      12.50      13.53     -1.030 1.766e+004 9.358e+005      1.000 
 
 
*) Starred values were included in the estimation of Lambda_z. 
 
 
Final Parameters 
--------------- 
Rsq                                                       0.9974 
Rsq_adjusted                                              0.9969 
Corr_XY                                                  -0.9987 
No_points_lambda_z                                        8 
Lambda_z                                1/h               0.0217 
Lambda_z_lower                            h              36.0000 
Lambda_z_upper                            h             168.5833 
HL_Lambda_z                               h              31.9880 
Tlag                                      h               2.0167 
Tmax                                      h              24.0000 
Cmax                                  ng/mL             266.0000 
Cmax_D                             ng/mL/mg               0.5911 
Tlast                                     h             168.5833 
Clast                                 ng/mL              12.5000 
AUClast                             h*ng/mL           17659.8509 
AUCall                              h*ng/mL           17659.8509 
AUCINF_obs                          h*ng/mL           18236.7130 
AUCINF_D_obs                     h*ng/mL/mg              40.5260 
AUC_%Extrap_obs                           %               3.1632 
Vz_F_obs                                  L            1138.7488 
Cl_F_obs                                L/h              24.6755 
AUCINF_pred                         h*ng/mL           18284.2270 
AUCINF_D_pred                    h*ng/mL/mg              40.6316 
AUC_%Extrap_pred                          %               3.4148 
Vz_F_pred                                 L            1135.7896 
Cl_F_pred                               L/h              24.6114 
AUMClast                          h*h*ng/mL          935816.7068 
AUMCINF_obs                       h*h*ng/mL         1059687.6338 
AUMC_%Extrap_obs                          %              11.6894 
AUMCINF_pred                      h*h*ng/mL         1069890.4303 
AUMC_%Extrap_pred                         %              12.5315 
MRTlast                                   h              52.9912 
MRTINF_obs                                h              58.1074 
MRTINF_pred                               h              58.5144 
AUC0_24                             h*ng/mL            4170.0975 
 
 
 
WinNonlin 7.0.0.2535 
Page 99 of 331


P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 2, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 4  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0        1 7. 5 0                            4. 3 7 5      6. 5 6 3  
      2. 0 0 0        2 0. 2 0                            1 3. 8 0      2 3. 2 3  
      3. 0 0 0        7 0. 4 0                            5 9. 1 0      1 4 9. 0  
      4. 0 0 0        1 0 6. 0                            1 4 7. 3      4 6 6. 6  
      6. 0 0 0        2 0 2. 0                            4 5 5. 3      2 1 0 3.  
      8. 0 0 0        2 0 3. 0                            8 6 0. 3      4 9 3 9.  
      1 2. 0 0        1 7 2. 0                            1 6 0 9. 1. 2 3 8 e + 0 0 4  
      1 6. 0 0        1 4 7. 0                            2 2 4 5. 2. 1 2 6 e + 0 0 4  
      2 4. 0 0        1 2 9. 0                            3 3 4 8. 4. 3 2 1 e + 0 0 4  
      3 6. 0 0 *      1 2 2. 0      1 1 9. 3      2. 7 3 3      4 8 5 3. 8. 8 3 0 e + 0 0 4      1. 0 0 0  
      4 8. 0 0 *      8 6. 3 0      8 7. 7 8     -1. 4 7 9      6 0 9 1. 1. 3 9 8 e + 0 0 5      1. 0 0 0  
      6 0. 0 0 *      6 4. 4 0      6 4. 6 0    -0. 2 0 4 9      6 9 8 9. 1. 8 8 1 e + 0 0 5      1. 0 0 0  
      7 2. 0 0 *      4 8. 4 0      4 7. 5 5     0. 8 5 1 4      7 6 6 1. 2. 3 2 2 e + 0 0 5      1. 0 0 0  
      9 6. 0 0 *      2 5. 3 0      2 5. 7 6    -0. 4 5 6 2      8 5 1 5. 3. 0 2 9 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      1 3. 4 0      1 3. 9 5    -0. 5 5 1 7      8 9 6 5. 3. 5 0 9 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      7. 8 5 0      7. 5 5 7     0. 2 9 2 6      9 2 1 4. 3. 8 3 5 e + 0 0 5      1. 0 0 0  
      1 6 8. 0       0. 0 0 0 0                            9 3 0 8. 3. 9 7 1 e + 0 0 5  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 9 3  
R s q _ a dj u st e d                                              0. 9 9 9 1  
C orr _ X Y                                                  -0. 9 9 9 6  
N o _ p oi nt s _l a m b d a _ z                                        7  
L a m b d a _ z                                1/ h               0. 0 2 5 5  
L a m b d a _ z _l o w er                            h              3 6. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 4 4. 0 0 0 0  
H L _ L a m b d a _ z                               h              2 7. 1 3 4 6  
Tl a g                                      h               1. 0 0 0 0  
T m a x                                      h               8. 0 0 0 0  
C m a x                                  n g/ m L             2 0 3. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 4 5 1 1  
Tl a st                                     h             1 4 4. 0 0 0 0  
Cl a st                                  n g/ m L               7. 8 5 0 0  
A U Cl a st                             h* n g/ m L            9 2 1 3. 9 2 8 8  
A U C all                              h* n g/ m L            9 3 0 8. 1 2 8 8  
A U CI N F _ o b s                          h* n g/ m L            9 5 2 1. 2 3 2 0  
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A U CI N F _ D _ o b s                     h* n g/ m L/ m g              2 1. 1 5 8 3  
A U C _ % E xtr a p _ o b s                           %               3. 2 2 7 6  
V z _ F _ o b s                                  L            1 8 5 0. 1 9 1 7  
Cl _ F _ o b s                                L/ h              4 7. 2 6 2 8  
A U CI N F _ pr e d                         h* n g/ m L            9 5 0 9. 7 7 7 2  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              2 1. 1 3 2 8  
A U C _ % E xtr a p _ pr e d                          %               3. 1 1 1 0  
V z _ F _ pr e d                                 L            1 8 5 2. 4 2 0 3  
Cl _ F _ pr e d                               L/ h              4 7. 3 1 9 7  
A U M Cl a st                          h* h* n g/ m L          3 8 3 5 0 6. 7 8 1 2  
A U M CI N F _ o b s                       h* h* n g/ m L          4 3 9 7 8 8. 4 0 2 0  
A U M C _ % E xtr a p _ o b s                          %              1 2. 7 9 7 4  
A U M CI N F _ pr e d                      h* h* n g/ m L          4 3 7 6 9 0. 4 8 5 6  
A U M C _ % E xtr a p _ pr e d                         %              1 2. 3 7 9 5  
M R Tl a st                                   h              4 1. 6 2 2 5  
M R TI N F _ o b s                                h              4 6. 1 9 0 3  
M R TI N F _ pr e d                               h              4 6. 0 2 5 3  
A U C 0 _ 2 4                             h* n g/ m L            3 3 4 7. 7 1 3 1  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 2, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 3  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0        5. 3 3 0                           0. 6 6 6 3     0. 4 9 9 7  
      1. 0 1 7        9. 2 6 0                            2. 6 1 2      2. 2 8 8  
      1. 5 0 0        1 7. 8 0                            9. 1 5 1      1 1. 0 2  
      2. 0 0 0        4 6. 0 0                            2 5. 1 0      4 0. 6 9  
      3. 0 0 0        8 3. 4 0                            8 9. 8 0      2 1 1. 8  
      4. 0 0 0        1 1 5. 0                            1 8 9. 0      5 6 6. 9  
      6. 0 0 0        2 4 5. 0                            5 4 9. 0      2 4 9 7.  
      8. 0 0 0        2 6 3. 0                            1 0 5 7.      6 0 7 1.  
      1 2. 0 0        2 5 7. 0                            2 0 9 7. 1. 6 4 6 e + 0 0 4  
      1 6. 0 0        2 7 0. 0                            3 1 5 1. 3. 1 2 7 e + 0 0 4  
      2 4. 0 2        2 7 9. 0                            5 3 5 2. 7. 5 4 4 e + 0 0 4  
      3 6. 0 0        2 6 1. 0                            8 5 8 6. 1. 7 2 3 e + 0 0 5  
      4 8. 0 0        2 5 5. 0                       1. 1 6 8 e + 0 0 4 3. 0 2 2 e + 0 0 5  
      6 0. 0 0        2 0 1. 0                       1. 4 4 0 e + 0 0 4 4. 4 8 6 e + 0 0 5  
      7 2. 0 0        1 7 4. 0                       1. 6 6 5 e + 0 0 4 5. 9 6 6 e + 0 0 5  
      9 6. 0 0        9 5. 4 0                       1. 9 7 9 e + 0 0 4 8. 5 6 5 e + 0 0 5  
      1 2 0. 0 *      4 9. 0 0      4 8. 8 4     0. 1 5 5 1 2. 1 4 6 e + 0 0 4 1. 0 3 5 e + 0 0 6      1. 0 0 0  
      1 4 4. 0 *      3 0. 8 0      3 1. 0 0    -0. 1 9 5 6 2. 2 4 0 e + 0 0 4 1. 1 5 8 e + 0 0 6      1. 0 0 0  
      1 6 8. 1 *      1 9. 7 0      1 9. 6 4    0. 0 6 2 1 5 2. 3 0 0 e + 0 0 4 1. 2 5 1 e + 0 0 6      1. 0 0 0  
 
 
Pa ge 1 0 1 of 3 3 1
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*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 9 9  
R s q _ a dj u st e d                                              0. 9 9 9 7  
C orr _ X Y                                                   - 0. 9 9 9 9  
N o _ p oi nt s _l a m b d a _ z                                        3  
L a m b d a _ z                                1/ h               0. 0 1 9 0  
L a m b d a _ z _l o w er                            h             1 2 0. 0 3 3 3  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 5 0 0  
H L _ L a m b d a _ z                               h              3 6. 5 2 6 5  
Tl a g                                      h               0. 5 0 0 0  
T m a x                                      h              2 4. 0 1 6 7  
C m a x                                  n g/ m L             2 7 9. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 6 2 0 0  
Tl a st                                     h             1 6 8. 0 5 0 0  
Cl a st                                 n g/ m L              1 9. 7 0 0 0  
A U Cl a st                             h* n g/ m L           2 3 0 0 0. 4 0 3 0  
A U C all                              h* n g/ m L           2 3 0 0 0. 4 0 3 0  
A U CI N F _ o b s                          h* n g/ m L           2 4 0 3 8. 5 2 6 4  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              5 3. 4 1 8 9  
A U C _ % E xtr a p _ o b s                           %               4. 3 1 8 6  
V z _ F _ o b s                                  L             9 8 6. 4 7 8 0  
Cl _ F _ o b s                                L/ h              1 8. 7 1 9 9  
A U CI N F _ pr e d                         h* n g/ m L           2 4 0 3 5. 2 5 1 4  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              5 3. 4 1 1 7  
A U C _ % E xtr a p _ pr e d                          %               4. 3 0 5 5  
V z _ F _ pr e d                                 L             9 8 6. 6 1 2 4  
Cl _ F _ pr e d                               L/ h              1 8. 7 2 2 5  
A U M Cl a st                          h* h* n g/ m L         1 2 5 0 8 7 8. 2 5 1 8  
A U M CI N F _ o b s                       h* h* n g/ m L         1 4 8 0 0 4 0. 4 7 3 9  
A U M C _ % E xtr a p _ o b s                          %              1 5. 4 8 3 5  
A U M CI N F _ pr e d                      h* h* n g/ m L         1 4 7 9 3 1 7. 5 4 1 4  
A U M C _ % E xtr a p _ pr e d                         %              1 5. 4 4 2 2  
M R Tl a st                                   h              5 4. 3 8 5 1  
M R TI N F _ o b s                                h              6 1. 5 6 9 5  
M R TI N F _ pr e d                               h              6 1. 5 4 7 8  
A U C 0 _ 2 4                             h* n g/ m L            5 3 4 6. 8 8 0 1  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 2, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 1  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   1 8  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
Pa ge 1 0 2 of 3 3 1
PI
PI


     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0        5. 0 0 0                           0. 6 2 5 0     0. 4 6 8 8  
      1. 0 0 0        1 0. 3 0                            2. 5 3 8      2. 2 2 5  
      1. 5 0 0        2 2. 0 0                            1 0. 6 1      1 3. 0 5  
      2. 0 0 0        3 8. 8 0                            2 5. 8 1      4 0. 7 0  
      3. 0 0 0        1 0 7. 0                            9 8. 7 1      2 4 0. 0  
      4. 0 0 0        1 4 3. 0                            2 2 3. 7      6 8 6. 5  
      6. 0 0 0        2 4 4. 0                            6 1 0. 7      2 7 2 3.  
      8. 0 0 0        2 4 0. 0                            1 0 9 5.      6 1 0 9.  
      1 2. 0 0        2 0 1. 0                            1 9 7 4. 1. 4 8 5 e + 0 0 4  
      1 6. 0 0        1 4 7. 0                            2 6 6 5. 2. 4 4 5 e + 0 0 4  
      2 4. 0 0        1 1 2. 0                            3 6 9 4. 4. 4 8 5 e + 0 0 4  
      3 6. 0 0        9 2. 6 0                            4 9 1 8. 8. 1 3 4 e + 0 0 4  
      4 8. 0 0 *      6 8. 8 0      6 8. 4 7     0. 3 3 2 4      5 8 8 0. 1. 2 1 4 e + 0 0 5      1. 0 0 0  
      6 0. 0 0 *       5 4. 9 0      5 5. 4 3    -0. 5 3 4 4      6 6 1 9. 1. 6 1 2 e + 0 0 5      1. 0 0 0  
      7 2. 0 0 *      4 5. 1 0      4 4. 8 8     0. 2 1 7 9      7 2 1 7. 2. 0 0 5 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 8 4  
R s q _ a dj u st e d                                              0. 9 9 6 8  
C orr _ X Y                                                  -0. 9 9 9 2  
N o _ p oi nt s _l a m b d a _ z                                        3  
L a m b d a _ z                                1/ h               0. 0 1 7 6  
L a m b d a _ z _l o w er                            h              4 8. 0 0 0 0  
L a m b d a _ z _ u p p er                            h              7 2. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 9. 3 9 0 7  
Tl a g                                      h               0. 5 0 0 0  
T m a x                                      h               6. 0 0 0 0  
C m a x                                  n g/ m L             2 4 4. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 5 4 2 2  
Tl a st                                     h              7 2. 0 0 0 0  
Cl a st                                 n g/ m L              4 5. 1 0 0 0  
A U Cl a st                             h* n g/ m L            7 2 1 6. 8 2 9 2  
A U C all                              h* n g/ m L            7 2 1 6. 8 2 9 2  
A U CI N F _ o b s                          h* n g/ m L            9 7 7 9. 8 0 5 5  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              2 1. 7 3 2 9  
A U C _ % E xtr a p _ o b s                           %              2 6. 2 0 6 8  
V z _ F _ o b s                                  L            2 6 1 4. 8 7 1 5  
Cl _ F _ o b s                                L/ h              4 6. 0 1 3 2  
A U CI N F _ pr e d                         h* n g/ m L            9 7 6 7. 4 2 2 5  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              2 1. 7 0 5 4  
A U C _ % E xtr a p _ pr e d                          %              2 6. 1 1 3 3  
V z _ F _ pr e d                                 L            2 6 1 8. 1 8 6 6  
Cl _ F _ pr e d                               L/ h              4 6. 0 7 1 5  
A U M Cl a st                          h* h* n g/ m L          2 0 0 5 2 8. 3 4 5 8  
A U M CI N F _ o b s                       h* h* n g/ m L          5 3 0 7 1 3. 3 6 4 1  
A U M C _ % E xtr a p _ o b s                          %              6 2. 2 1 5 3  
A U M CI N F _ pr e d                      h* h* n g/ m L          5 2 9 1 1 8. 0 7 3 1  
A U M C _ % E xtr a p _ pr e d                         %              6 2. 1 0 1 4  
M R Tl a st                                   h              2 7. 7 8 6 2  
M R TI N F _ o b s                                h              5 4. 2 6 6 2  
M R TI N F _ pr e d                               h              5 4. 1 7 1 7  
A U C 0 _ 2 4                             h* n g/ m L            3 6 9 4. 4 3 7 5  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 1, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 3  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
Pa ge 1 0 3 of 3 3 1
PI
PI


-------- 
Model:  Plasma Data, Extravascular Administration 
Number of nonmissing observations:   22 
Dose time:      0.00 
Dose amount:      450.00 
Calculation method:  Linear Trapezoidal Rule for for Increasing Values, 
                     Log Trapezoidal Rule for Decreasing Values 
Weighting for lambda_z calculations:  Uniform weighting 
Lambda_z method:  Find best fit for lambda_z,  Log regression 
 
 
Summary Table 
------------- 
      Time         Conc.      Pred.    Residual      AUC       AUMC      Weight 
          h       ng/mL       ng/mL       ng/mL     h*ng/mL   h*h*ng/mL 
------------------------------------------------------------------------------- 
     0.0000       0.0000                           0.0000     0.0000 
     0.2500       0.0000                           0.0000     0.0000 
     0.5000       0.0000                           0.0000     0.0000 
     0.8167       0.0000                           0.0000     0.0000 
      1.017        5.950                           0.5950     0.6049 
      1.500        15.50                            5.779      7.686 
      2.000        31.60                            17.55      29.30 
      3.000        105.0                            85.85      218.4 
      4.000        138.0                            207.4      651.9 
      6.000        211.0                            556.4      2470. 
      8.033        221.0                            995.6      5562. 
      12.00 *      185.0      179.0      5.980      1799. 1.356e+004      1.000 
      16.00 *      163.0      163.9    -0.8673      2494. 2.326e+004      1.000 
      24.00 *      125.0      137.3     -12.30      3639. 4.596e+004      1.000 
      36.00 *      111.0      105.3      5.695      5053. 8.823e+004      1.000 
      48.02 *      81.60      80.73     0.8652      6202. 1.361e+005      1.000 
      60.08 *      69.40      61.83      7.571      7111. 1.851e+005      1.000 
      72.00 *      43.00      47.51     -4.508      7768. 2.282e+005      1.000 
      95.73 *      29.80      28.11      1.689      8622. 2.992e+005      1.000 
      120.1 *      15.00      16.39     -1.390      9148. 3.553e+005      1.000 
      144.0 *      9.050      9.670    -0.6195      9429. 3.921e+005      1.000 
      171.8 *      5.690      5.233     0.4566      9630. 4.236e+005      1.000 
 
 
*) Starred values were included in the estimation of Lambda_z. 
 
 
Final Parameters 
--------------- 
Rsq                                                       0.9959 
Rsq_adjusted                                              0.9954 
Corr_XY                                                  -0.9979 
No_points_lambda_z                                       11 
Lambda_z                                1/h               0.0221 
Lambda_z_lower                            h              12.0000 
Lambda_z_upper                            h             171.7667 
HL_Lambda_z                               h              31.3500 
Tlag                                      h               0.8167 
Tmax                                      h               8.0333 
Cmax                                  ng/mL             221.0000 
Cmax_D                             ng/mL/mg               0.4911 
Tlast                                     h             171.7667 
Clast                                 ng/mL               5.6900 
AUClast                             h*ng/mL            9630.2797 
AUCall                              h*ng/mL            9630.2797 
AUCINF_obs                          h*ng/mL            9887.6296 
AUCINF_D_obs                     h*ng/mL/mg              21.9725 
AUC_%Extrap_obs                           %               2.6027 
Vz_F_obs                                  L            2058.4109 
Cl_F_obs                                L/h              45.5114 
AUCINF_pred                         h*ng/mL            9866.9780 
AUCINF_D_pred                    h*ng/mL/mg              21.9266 
AUC_%Extrap_pred                          %               2.3989 
Vz_F_pred                                 L            2062.7191 
Cl_F_pred                               L/h              45.6067 
AUMClast                          h*h*ng/mL          423629.2804 
AUMCINF_obs                       h*h*ng/mL          479472.9530 
Page 104 of 331


A U M C _ % E xtr a p _ o b s                          %              1 1. 6 4 6 9  
A U M CI N F _ pr e d                      h* h* n g/ m L          4 7 4 9 9 1. 6 5 7 0  
A U M C _ % E xtr a p _ pr e d                         %              1 0. 8 1 3 3  
M R Tl a st                                   h              4 3. 9 8 9 3  
M R TI N F _ o b s                                h              4 8. 4 9 2 2  
M R TI N F _ pr e d                               h              4 8. 1 3 9 5  
A U C 0 _ 2 4                             h* n g/ m L            3 6 3 9. 0 2 7 6  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 1, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 3  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m  w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      2. 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      3. 0 0 0        1 1. 6 0                            5. 8 0 0      1 7. 4 0  
      4. 0 0 0        3 0. 2 0                            2 6. 7 0      9 5. 2 0  
      6. 0 0 0        1 0 6. 0                            1 6 2. 9      8 5 2. 0  
      8. 0 0 0        1 0 9. 0                            3 7 7. 9      2 3 6 0.  
      1 2. 0 0        1 0 0. 0                            7 9 5. 6      6 5 2 5.  
      1 6. 0 0        9 0. 5 0                            1 1 7 6. 1. 1 8 4 e + 0 0 4  
      2 4. 0 0        1 0 0. 0                            1 9 3 8. 2. 7 2 3 e + 0 0 4  
      3 6. 0 0 *      9 6. 7 0      9 4. 4 1      2. 2 8 6      3 1 1 8. 6. 2 6 0 e + 0 0 4      1. 0 0 0  
      4 8. 0 0 *      6 8. 6 0      7 1. 0 8     -2. 4 8 0      4 1 0 1. 1. 0 3 5 e + 0 0 5      1. 0 0 0  
      60. 0 0 *      5 1. 9 0      5 3. 5 1     -1. 6 1 3      4 8 1 9. 1. 4 2 1 e + 0 0 5      1. 0 0 0  
      7 2. 0 0 *      4 1. 0 0      4 0. 2 9     0. 7 1 2 5      5 3 7 4. 1. 7 8 6 e + 0 0 5      1. 0 0 0  
      9 6. 0 0 *      2 4. 1 0      2 2. 8 3      1. 2 6 5      6 1 3 7. 2. 4 1 9 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      1 2. 7 0      1 2. 9 4    -0. 2 4 2 4      6 5 6 4. 2. 8 7 5 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      7. 2 6 0      7. 3 3 6   -0. 0 7 5 5 9      6 7 9 8. 3. 1 8 0 e + 0 0 5      1. 0 0 0  
      1 6 8. 0       0. 0 0 0 0                            6 8 8 5. 3. 3 0 6 e + 0 0 5  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 8 8  
R s q _ a dj u st e d                                              0. 9 9 8 5  
C orr _ X Y                                                  -0. 9 9 9 4  
N o _ p oi nt s _l a m b d a _ z                                        7  
L a m b d a _ z                                1/ h               0. 0 2 3 7  
L a m b d a _ z _l o w er                            h              3 6. 0 0 0 0  
Pa ge 1 0 5 of 3 3 1
PI
PI


L a m b d a _ z _ u p p er                            h             1 4 4. 0 0 0 0  
H L _ L a m b d a _ z                               h              2 9. 2 9 9 9  
Tl a g                                      h               2. 0 0 0 0  
T m a x                                      h               8. 0 0 0 0  
C m a x                                  n g/ m L             1 0 9. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 2 4 2 2  
Tl a st                                     h             1 4 4. 0 0 0 0  
Cl a st                                 n g/ m L               7. 2 6 0 0  
A U Cl a st                             h* n g/ m L            6 7 9 7. 6 5 0 4  
A U C all                              h* n g/ m L            6 8 8 4. 7 7 0 4  
A U CI N F _ o b s                          h* n g/ m L            7 1 0 4. 5 3 6 2  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              1 5. 7 8 7 9  
A U C _ % E xtr a p _ o b s                           %               4. 3 1 9 6  
V z _ F _ o b s                                  L            2 6 7 7. 4 2 2 9  
Cl _ F _ o b s                                L/ h              6 3. 3 3 9 8  
A U CI N F _ pr e d                         h* n g/ m L            7 1 0 7. 7 3 1 3  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              1 5. 7 9 5 0  
A U C _ % E xtr a p _ pr e d                          %               4. 3 6 2 6  
V z _ F _ pr e d                                 L            2 6 7 6. 2 1 9 3  
Cl _ F _ pr e d                               L/ h              6 3. 3 1 1 3  
A U M Cl a st                          h* h* n g/ m L          3 1 8 0 4 3. 2 1 4 2  
A U M CI N F _ o b s                       h* h* n g/ m L          3 7 5 2 0 7. 0 7 2 1  
A U M C _ % E xtr a p _ o b s                          %              1 5. 2 3 5 3  
A U M CI N F _ pr e d                      h* h* n g/ m L          3 7 5 8 0 2. 2 3 9 4  
A U M C _ % E xtr a p _ pr e d                         %              1 5. 3 6 9 5  
M R Tl a st                                   h              4 6. 7 8 7 2  
M R TI N F _ o b s                                h              5 2. 8 1 2 3  
M R TI N F _ pr e d                               h              5 2. 8 7 2 3  
A U C 0 _ 2 4                             h* n g/ m L            1 9 3 8. 3 2 5 5  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 1, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 2  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s e r v ati o n s:   2 2 
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0        7. 2 9 0                           0. 9 1 1 3     0. 9 1 1 3  
      1. 5 0 0        1 5. 7 0                            6. 6 5 9      8. 6 2 1  
      2. 0 0 0        3 5. 7 0                            1 9. 5 1      3 2. 3 6  
      3. 0 0 0        7 8. 5 0                            7 6. 6 1      1 8 5. 8  
      4. 0 0 0        1 0 6. 0                            1 6 8. 9      5 1 5. 6  
      6. 0 0 0        1 7 5. 0                            4 4 9. 9      1 9 9 0 . 
      8. 0 1 7        2 1 4. 0                            8 4 2. 1      4 7 7 8.  
      1 2. 0 0        2 4 6. 0                            1 7 5 8. 1. 4 0 7 e + 0 0 4  
      1 6. 0 0        2 5 2. 0                            2 7 5 4. 2. 8 0 4 e + 0 0 4  
Pa ge 1 0 6 of 3 3 1
PI
PI


      2 4. 0 0        2 6 2. 0                            4 8 1 0. 6. 9 3 2 e + 0 0 4  
      3 6. 0 0        2 6 7. 0                            7 9 8 4. 1. 6 4 7 e + 0 0 5  
      4 8. 0 0        2 8 1. 0                       1. 1 2 7 e + 0 0 4 3. 0 3 3 e + 0 0 5  
      6 0. 0 3        2 4 5. 0                       1. 4 4 3 e + 0 0 4 4. 7 3 6 e + 0 0 5  
      7 2. 0 0        2 0 1. 0                       1. 7 0 9 e + 0 0 4 6. 4 8 6 e + 0 0 5  
      9 6. 0 3 *      1 0 5. 0      1 0 3. 5      1. 5 1 1 2. 0 6 5 e + 0 0 4 9. 4 2 6 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      6 4. 5 0      6 5. 1 7    -0. 6 7 4 7 2. 2 6 4 e + 0 0 4 1. 1 5 6 e + 0 0 6      1. 0 0 0  
      1 4 4. 0 *      4 0. 1 0      4 1. 0 2    -0. 9 1 9 0 2. 3 8 7 e + 0 0 4 1. 3 1 7 e + 0 0 6      1. 0 0 0  
      1 6 8. 0 *      2 6. 3 0      2 5. 8 2     0. 4 8 3 8 2. 4 6 5 e + 0 0 4 1. 4 3 9 e + 0 0 6      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 8 9  
R s q _ a dj u st e d                                              0. 9 9 8 4  
C orr _ X Y                                                  -0. 9 9 9 5  
N o _ p oi nt s _l a m b d a _ z                                        4  
L a m b d a _ z                                1/ h               0. 0 1 9 3  
L a m b d a _ z _l o w er                            h              9 6. 0 3 3 3  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 5. 9 2 7 1  
Tl a g                                      h               0. 7 5 0 0  
T m a x                                      h              4 8. 0 0 0 0  
C m a x                                  n g/ m L             2 8 1. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 6 2 4 4  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L              2 6. 3 0 0 0  
A U Cl a st                             h* n g/ m L           2 4 6 5 4. 2 9 3 3  
A U C all                              h* n g/ m L           2 4 6 5 4. 2 9 3 3  
A U CI N F _ o b s                          h* n g/ m L           2 6 0 1 7. 4 7 2 6  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              5 7. 8 1 6 6  
A U C _ % E xtr a p _ o b s                           %               5. 2 3 9 5  
V z _ F _ o b s                                  L             8 9 6. 4 8 8 3  
Cl _ F _ o b s                                L/ h              1 7. 2 9 6 1  
A U CI N F _ pr e d                         h* n g/ m L           2 5 9 9 2. 3 9 4 2  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              5 7. 7 6 0 9  
A U C _ % E xtr a p _ pr e d                          %               5. 1 4 8 0  
V z _ F _ pr e d                                 L             8 9 7. 3 5 3 3  
Cl _ F _ pr e d                               L/ h              1 7. 3 1 2 8  
A U M Cl a st                          h* h* n g/ m L         1 4 3 9 1 0 3. 8 5 7 0  
A U M CI N F _ o b s                       h* h* n g/ m L         1 7 3 8 7 7 4. 1 5 6 5  
A U M C _ % E xtr a p _ o b s                          %              1 7. 2 3 4 6  
A U M CI N F _ pr e d                      h* h* n g/ m L         1 7 3 3 2 6 1. 1 3 7 6  
A U M C _ % E xtr a p _ pr e d                         %              1 6. 9 7 1 3  
M R Tl a st                                   h              5 8. 3 7 1 3  
M R TI N F _ o b s                                h              6 6. 8 3 1 0  
M R TI N F _ pr e d                               h              6 6. 6 8 3 4  
A U C 0 _ 2 4                             h* n g/ m L            4 8 1 0. 2 6 7 1  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 2, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 2  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
Pa ge 1 0 7 of 3 3 1
PI
PI


Weighting for lambda_z calculations:  Uniform weighting 
Lambda_z method:  Find best fit for lambda_z,  Log regression 
 
 
Summary Table 
------------- 
      Time         Conc.      Pred.    Residual      AUC       AUMC      Weight 
          h       ng/mL       ng/mL       ng/mL     h*ng/mL   h*h*ng/mL 
------------------------------------------------------------------------------- 
     0.0000       0.0000                           0.0000     0.0000 
     0.2667       0.0000                           0.0000     0.0000 
     0.5000       0.0000                           0.0000     0.0000 
     0.7500       0.0000                           0.0000     0.0000 
      1.000        5.360                           0.6700     0.6700 
      1.500        16.80                            6.210      8.310 
      2.000        47.80                            22.36      38.51 
      3.000        70.10                            81.31      191.5 
      4.000        127.0                            179.9      550.6 
      6.000        238.0                            544.9      2487. 
      8.000        356.0                            1139.      6763. 
      12.00        390.0                            2631. 2.182e+004 
      16.00        407.0                            4225. 4.420e+004 
      24.00        408.0                            7485. 1.094e+005 
      36.00 *      307.0      317.0     -10.01 1.175e+004 2.360e+005      1.000 
      48.00 *      255.0      245.7      9.344 1.511e+004 3.766e+005      1.000 
      60.00 *      184.0      190.4     -6.365 1.772e+004 5.168e+005      1.000 
      72.00 *      159.0      147.5      11.48 1.977e+004 6.521e+005      1.000 
      96.00 *      85.60      88.59     -2.986 2.262e+004 8.875e+005      1.000 
      120.0 *      52.90      53.20    -0.2966 2.425e+004 1.062e+006      1.000 
      144.0 *      30.60      31.94     -1.345 2.523e+004 1.190e+006      1.000 
      168.0 *      19.90      19.18     0.7168 2.582e+004 1.283e+006      1.000 
 
 
*) Starred values were included in the estimation of Lambda_z. 
 
 
Final Parameters 
--------------- 
Rsq                                                       0.9981 
Rsq_adjusted                                              0.9978 
Corr_XY                                                  -0.9990 
No_points_lambda_z                                        8 
Lambda_z                                1/h               0.0212 
Lambda_z_lower                            h              36.0000 
Lambda_z_upper                            h             168.0000 
HL_Lambda_z                               h              32.6200 
Tlag                                      h               0.7500 
Tmax                                      h              24.0000 
Cmax                                  ng/mL             408.0000 
Cmax_D                             ng/mL/mg               0.9067 
Tlast                                     h             168.0000 
Clast                                 ng/mL              19.9000 
AUClast                             h*ng/mL           25823.7962 
AUCall                              h*ng/mL           25823.7962 
AUCINF_obs                          h*ng/mL           26760.3056 
AUCINF_D_obs                     h*ng/mL/mg              59.4673 
AUC_%Extrap_obs                           %               3.4996 
Vz_F_obs                                  L             791.3717 
Cl_F_obs                                L/h              16.8160 
AUCINF_pred                         h*ng/mL           26726.5734 
AUCINF_D_pred                    h*ng/mL/mg              59.3924 
AUC_%Extrap_pred                          %               3.3778 
Vz_F_pred                                 L             792.3705 
Cl_F_pred                               L/h              16.8372 
AUMClast                          h*h*ng/mL         1282665.5070 
AUMCINF_obs                       h*h*ng/mL         1484071.9365 
AUMC_%Extrap_obs                          %              13.5712 
AUMCINF_pred                      h*h*ng/mL         1476817.4627 
AUMC_%Extrap_pred                         %              13.1466 
MRTlast                                   h              49.6699 
MRTINF_obs                                h              55.4580 
MRTINF_pred                               h              55.2565 
AUC0_24                             h*ng/mL            7484.8600 
Page 108 of 331


 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D =
, A P E RI O D = 2, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3 
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 2  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0        6. 7 4 0                           0. 8 4 2 5     0. 8 4 2 5  
      1. 5 0 0        1 5. 7 0                            6. 4 5 3      8. 4 1 5  
      2. 0 0 0        3 9. 4 0                            2 0. 2 3      3 4. 0 0  
      3. 0 0 0        8 8. 8 0                            8 4. 3 3      2 0 6. 6  
      4. 0 0 0        1 0 6. 0                            1 8 1. 7      5 5 1. 8  
      6. 0 1 7        1 6 8. 0                            4 5 8. 0      1 9 9 9.  
      8. 0 0 0        1 7 8. 0                            8 0 1. 1      4 4 1 3.  
      1 2. 0 0        1 8 2. 0                            1 5 2 1. 1. 1 6 3 e + 0 0 4  
      1 6. 1 0        1 9 0. 0                            2 2 8 4. 2. 2 3 8 e + 0 0 4  
      2 4. 0 7        1 8 7. 0                            3 7 8 5. 5. 2 5 2 e + 0 0 4  
      3 6. 0 0        1 7 9. 0                            5 9 6 9. 1. 1 8 0 e + 0 0 5  
      4 8. 0 0 *      1 4 9. 0      1 5 9. 1     -1 0. 1 2      7 9 3 1. 2. 0 0 1 e + 0 0 5      1. 0 0 0  
      6 0. 0 2 *      1 2 2. 0      1 2 0. 4      1. 6 3 1      9 5 5 4. 2. 8 7 4 e + 0 0 5      1. 0 0 0  
      7 2. 0 0 *      9 6. 7 0      9 1. 1 3      5. 5 7 3 1. 0 8 6 e + 0 0 4 3. 7 3 2 e + 0 0 5      1. 0 0 0  
      9 6. 1 7 *      5 5. 7 0      5 1. 9 9      3. 7 1 3 1. 2 6 5 e + 0 0 4 5. 2 2 2 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      2 8. 4 0      2 9. 8 9     -1. 4 8 9 1. 3 6 2 e + 0 0 4 6. 2 5 4 e + 0 0 5      1. 0 0 0  
      1 4 6. 9 *      1 4. 7 0      1 5. 9 9     -1. 2 9 0 1. 4 1 8 e + 0 0 4 6. 9 9 3 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      1 0. 4 0      9. 8 0 3     0. 5 9 6 8 1. 4 4 4 e + 0 0 4 7. 4 0 4 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 6 1  
R s q _ a dj u st e d                                              0. 9 9 5 3  
C orr _ X Y                                                  -0. 9 9 8 1  
N o _ p oi nt s _l a m b d a _ z                                        7  
L a m b d a _ z                                1/ h               0. 0 2 3 2  
L a m b d a _ z _l o w er                            h              4 8. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              2 9. 8 4 5 6  
Tl a g                                      h               0. 7 5 0 0  
T m a x                                      h              1 6. 1 0 0 0  
C m a x                                  n g/ m L             1 9 0. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 4 2 2 2  
Tl a st                                     h             1 6 8. 0 0 0 0  
Pa ge 1 0 9 of 3 3 1
PI
PI


Cl a st                                  n g/ m L              1 0. 4 0 0 0  
A U Cl a st                             h* n g/ m L           1 4 4 4 2. 9 4 4 0  
A U C all                              h* n g/ m L           1 4 4 4 2. 9 4 4 0  
A U CI N F _ o b s                          h* n g/ m L           1 4 8 9 0. 7 4 8 3  
A U CI N F _ D _ o b s                      h* n g/ m L/ m g              3 3. 0 9 0 6  
A U C _ % E xtr a p _ o b s                           %               3. 0 0 7 3  
V z _ F _ o b s                                  L            1 3 0 1. 2 2 0 6  
Cl _ F _ o b s                                L/ h              3 0. 2 2 0 1  
A U CI N F _ p r e d                         h* n g/ m L           1 4 8 6 5. 0 5 0 6 
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              3 3. 0 3 3 4  
A U C _ % E xtr a p _ pr e d                          %               2. 8 3 9 6  
V z _ F _ pr e d                                 L            1 3 0 3. 4 7 0 0  
Cl _ F _ pr e d                               L/ h              3 0. 2 7 2 3  
A U M Cl a st                          h* h* n g/ m L          7 4 0 3 8 2. 3 4 8 4  
A U M CI N F _ o b s                       h* h* n g/ m L          8 3 4 8 9 5. 0 7 7 7  
A U M C _ % E xtr a p _ o b s                          %              1 1. 3 2 0 3  
A U M CI N F _ pr e d                      h* h* n g/ m L          8 2 9 4 7 1. 3 8 2 3  
A U M C _ % E xtr a p _ pr e d                         %              1 0. 7 4 0 5  
M R Tl a st                                   h              5 1. 2 6 2 6  
M R TI N F _ o b s                                h              5 6. 0 6 8 0  
M R TI N F _ pr e d                               h              5 5. 8 0 0 1  
A U C 0 _ 2 4                             h* n g/ m L            3 7 7 2. 9 4 5 0  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 2, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 2  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0        7. 8 8 0                           0. 9 8 5 0     0. 9 8 5 0  
      1. 5 0 0        1 2. 8 0                            6. 1 5 5      7. 7 5 5  
      2. 0 0 0        2 3. 7 0                            1 5. 2 8      2 4. 4 1  
      3. 0 0 0        7 4. 6 0                            6 4. 4 3      1 6 0. 0  
      4. 0 0 0        1 2 1. 0                            1 6 2. 2      5 1 3. 9  
      6. 0 0 0        2 1 5. 0                            4 9 8. 2      2 2 8 8.  
      8. 0 0 0        2 3 1. 0                            9 4 4. 2      5 4 2 6.  
      1 2. 0 0        2 1 0. 0                            1 8 2 6. 1. 4 2 1 e + 0 0 4  
      1 6. 0 0        1 8 6. 0                            2 6 1 7. 2. 5 2 5 e + 0 0 4  
      2 4. 0 2        1 6 6. 0                            4 0 2 6. 5. 3 3 5 e + 0 0 4  
      3 6. 0 0        1 8 9. 0                            6 1 5 3. 1. 1 8 0 e + 0 0 5  
      4 8. 0 0        1 7 5. 0                            8 3 3 6. 2. 0 9 5 e + 0 0 5  
      6 0. 0 0        1 5 6. 0                       1. 0 3 2 e + 0 0 4 3. 1 6 4 e + 0 0 5  
      7 2. 0 0        1 1 8. 0                       1. 1 9 5 e + 0 0 4 4. 2 3 8 e + 0 0 5  
      9 6. 0 0        9 2. 7 0                       1. 4 4 7 e + 0 0 4 6. 3 3 9 e + 0 0 5  
      1 2 0. 0 *      5 4. 6 0      5 4. 4 5     0. 1 5 3 1 1. 6 2 0 e + 0 0 4 8. 1 8 8 e + 0 0 5      1. 0 0 0  
Pa ge 1 1 0 of 3 3 1
PI
PI


      1 4 4. 0 *      3 3. 1 0      3 3. 2 9    -0. 1 8 6 4 1. 7 2 3 e + 0 0 4 9. 5 3 8 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      2 0. 4 0      2 0. 3 4    0. 0 5 7 1 7 1. 7 8 6 e + 0 0 4 1. 0 5 1 e + 0 0 6      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 9 9  
R s q _ a dj u st e d                                              0. 9 9 9 8  
C orr _ X Y                                                  - 1. 0 0 0 0  
N o _ p oi nt s _l a m b d a _ z                                        3  
L a m b d a _ z                                1/ h               0. 0 2 0 5  
L a m b d a _ z _l o w er                            h             1 2 0. 0 1 6 7  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 3. 7 8 3 3  
Tl a g                                      h               0. 7 5 0 0  
T m a x                                      h               8. 0 0 0 0  
C m a x                                  n g/ m L             2 3 1. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 5 1 3 3  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L              2 0. 4 0 0 0  
A U Cl a st                             h* n g/ m L           1 7 8 5 8. 0 5 1 1  
A U C all                              h* n g/ m L           1 7 8 5 8. 0 5 1 1  
A U CI N F _ o b s                          h* n g/ m L           1 8 8 5 2. 3 2 5 3  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              4 1. 8 9 4 1  
A U C _ % E xtr a p _ o b s                           %               5. 2 7 4 0  
V z _ F _ o b s                                  L            1 1 6 3. 3 8 5 4  
Cl _ F _ o b s                                L/ h              2 3. 8 6 9 7  
A U CI N F _ pr e d                         h* n g/ m L           1 8 8 4 9. 5 3 8 9  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              4 1. 8 8 7 9  
A U C _ % E xtr a p _ pr e d                          %               5. 2 6 0 0  
V z _ F _ pr e d                                 L            1 1 6 3. 5 5 7 3  
Cl _ F _ pr e d                               L/ h              2 3. 8 7 3 3  
A U M Cl a st                          h* h* n g/ m L         1 0 5 1 4 0 7. 0 8 1 2  
A U M CI N F _ o b s                       h* h* n g/ m L         1 2 6 6 9 0 5. 0 0 9 2  
A U M C _ % E xtr a p _ o b s                          %              1 7. 0 0 9 8  
A U M CI N F _ pr e d                      h* h* n g/ m L         1 2 6 6 3 0 1. 0 8 6 3  
A U M C _ % E xtr a p _ pr e d                         %              1 6. 9 7 0 2  
M R Tl a st                                   h              5 8. 8 7 5 8  
M R TI N F _ o b s                                h              6 7. 2 0 1 5  
M R TI N F _ pr e d                               h              6 7. 1 7 9 4  
A U C 0 _ 2 4                             h* n g/ m L            4 0 2 3. 2 3 9 0  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 2, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 3  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
Pa ge 1 1 1 of 3 3 1
PI
PI


          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0        6. 0 3 0                           0. 7 5 3 8     0. 7 5 3 8  
      1. 5 0 0        2 0. 5 0                            7. 3 8 6      9. 9 4 9  
      2. 0 0 0        3 5. 8 0                            2 1. 4 6      3 5. 5 4  
      3. 0 0 0        1 1 2. 0                            9 5. 3 6      2 3 9. 3  
      4. 0 0 0        1 7 6. 0                            2 3 9. 4      7 5 9. 3  
      6. 0 0 0        2 1 2. 0                            6 2 7. 4      2 7 3 5.  
      8. 0 0 0        2 2 4. 0                            1 0 6 3.      5 7 9 9.  
      1 2. 0 0        2 3 3. 0                            1 9 7 7. 1. 4 9 8 e + 0 0 4  
      1 6. 0 0        2 1 3. 0                            2 8 6 9. 2. 7 4 3 e + 0 0 4  
      2 4. 0 2        2 3 1. 0                            4 6 4 8. 6. 3 3 3 e + 0 0 4  
      3 6. 0 0        2 2 5. 0                            7 3 8 1. 1. 4 5 2 e + 0 0 5  
      4 8. 0 0        1 7 5. 0                            9 7 6 8. 2. 4 4 9 e + 0 0 5  
      6 0. 0 0        1 7 6. 0                       1. 1 8 7 e + 0 0 4 3. 5 8 7 e + 0 0 5  
      7 2. 0 0        1 6 4. 0                       1. 3 9 1 e + 0 0 4 4. 9 3 1 e + 0 0 5  
      9 6. 0 0        1 1 2. 0                       1. 7 1 9 e + 0 0 4 7. 6 5 5 e + 0 0 5  
      1 2 0. 0 *      5 9. 1 0      5 9. 2 0    -0. 1 0 4 1 1. 9 1 7 e + 0 0 4 9. 7 7 5 e + 0 0 5      1. 0 0 0 
      1 4 4. 0 *      3 5. 5 0      3 5. 3 8     0. 1 2 4 8 2. 0 2 8 e + 0 0 4 1. 1 2 3 e + 0 0 6      1. 0 0 0  
      1 6 8. 0 *      2 1. 1 0      2 1. 1 4   -0. 0 3 7 1 7 2. 0 9 5 e + 0 0 4 1. 2 2 6 e + 0 0 6      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       1. 0 0 0 0  
R s q _ a dj u st e d                                              0. 9 9 9 9  
C orr _ X Y                                                  -1. 0 0 0 0  
N o _ p oi nt s _l a m b d a _ z                                        3 
L a m b d a _ z                                1/ h               0. 0 2 1 5  
L a m b d a _ z _l o w er                            h             1 2 0. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 2. 3 0 3 3  
Tl a g                                      h               0. 7 5 0 0  
T m a x                                      h              1 2. 0 0 0 0  
C m a x                                  n g/ m L             2 3 3. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 5 1 7 8  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L              2 1. 1 0 0 0  
A U Cl a st                             h* n g/ m L           2 0 9 4 7. 0 9 0 2  
A U C all                              h* n g/ m L           2 0 9 4 7. 0 9 0 2  
A U CI N F _ o b s                          h* n g/ m L           2 1 9 3 0. 4 3 1 4  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              4 8. 7 3 4 3  
A U C _ % E xtr a p _ o b s                           %               4. 4 8 3 9  
V z _ F _ o b s                                  L             9 5 6. 2 8 4 5  
Cl _ F _ o b s                                L/ h              2 0. 5 1 9 4  
A U CI N F _ pr e d                         h* n g/ m L           2 1 9 3 2. 1 6 3 8  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              4 8. 7 3 8 1  
A U C _ % E xtr a p _ pr e d                          %               4. 4 9 1 5  
V z _ F _ pr e d                                 L             9 5 6. 2 0 8 9  
Cl _ F _ pr e d                               L/ h              2 0. 5 1 7 8  
A U M Cl a st                          h* h* n g/ m L         1 2 2 5 9 7 1. 4 6 8 6  
A U M CI N F _ o b s                       h* h* n g/ m L         1 4 3 7 0 0 0. 2 6 8 9  
A U M C _ % E xtr a p _ o b s                          %              1 4. 6 8 5 4  
A U M CI N F _ pr e d                      h* h* n g/ m L         1 4 3 7 3 7 2. 0 5 6 9  
A U M C _ % E xtr a p _ pr e d                         %              1 4. 7 0 7 4  
M R Tl a st                                   h              5 8. 5 2 7 1  
M R TI N F _ o b s                                h              6 5. 5 2 5 4  
M R TI N F _ pr e d                               h              6 5. 5 3 7 2  
A U C 0 _ 2 4                             h* n g/ m L            4 6 4 4. 6 1 3 3  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 2, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
Pa ge 1 1 2 of 3 3 1
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                                                  Time:     09:23:24 
 
 
                  WINNONLIN NONCOMPARTMENTAL ANALYSIS PROGRAM 
                                   7.0.0.2535 
                            Core Version 04Jun2007 
 
Settings 
-------- 
Model:  Plasma Data, Extravascular Administration 
Number of nonmissing observations:   22 
Dose time:      0.00 
Dose amount:      450.00 
Calculation method:  Linear Trapezoidal Rule for for Increasing Values, 
                     Log Trapezoidal Rule for Decreasing Values 
Weighting for lambda_z calculations:  Uniform weighting 
Lambda_z method:  Find best fit for lambda_z,  Log regression 
 
 
Summary Table 
------------- 
      Time         Conc.      Pred.    Residual      AUC       AUMC      Weight 
          h       ng/mL       ng/mL       ng/mL     h*ng/mL   h*h*ng/mL 
------------------------------------------------------------------------------- 
     0.0000       0.0000                           0.0000     0.0000 
     0.2500       0.0000                           0.0000     0.0000 
     0.5000       0.0000                           0.0000     0.0000 
     0.7500       0.0000                           0.0000     0.0000 
      1.000       0.0000                           0.0000     0.0000 
      1.500       0.0000                           0.0000     0.0000 
      2.000        5.820                            1.455      2.910 
      3.000        18.40                            13.57      36.33 
      4.000        45.60                            45.57      155.1 
      6.000        160.0                            251.2      1298. 
      8.000        178.0                            589.2      3682. 
      12.03        213.0                            1378. 1.172e+004 
      16.00 *      196.0      216.4     -20.39      2188. 2.306e+004      1.000 
      24.00 *      177.0      180.5     -3.550      3679. 5.278e+004      1.000 
      36.00 *      145.0      137.6      7.393      5605. 1.102e+005      1.000 
      48.00 *      113.0      104.9      8.122      7145. 1.745e+005      1.000 
      60.00 *      77.60      79.93     -2.334      8275. 2.351e+005      1.000 
      72.00 *      62.90      60.92      1.978      9115. 2.903e+005      1.000 
      96.07 *      37.90      35.34      2.565 1.030e+004 3.889e+005      1.000 
      120.1 *      21.70      20.53      1.167 1.100e+004 4.634e+005      1.000 
      144.0 *      9.490      11.94     -2.451 1.135e+004 5.096e+005      1.000 
      168.0 *      7.620      6.936     0.6836 1.156e+004 5.414e+005      1.000 
 
 
*) Starred values were included in the estimation of Lambda_z. 
 
 
Final Parameters 
--------------- 
Rsq                                                       0.9928 
Rsq_adjusted                                              0.9919 
Corr_XY                                                  -0.9964 
No_points_lambda_z                                       10 
Lambda_z                                1/h               0.0226 
Lambda_z_lower                            h              16.0000 
Lambda_z_upper                            h             168.0000 
HL_Lambda_z                               h              30.6248 
Tlag                                      h               1.5000 
Tmax                                      h              12.0333 
Cmax                                  ng/mL             213.0000 
Cmax_D                             ng/mL/mg               0.4733 
Tlast                                     h             168.0000 
Clast                                 ng/mL               7.6200 
AUClast                             h*ng/mL           11557.4808 
AUCall                              h*ng/mL           11557.4808 
AUCINF_obs                          h*ng/mL           11894.1496 
AUCINF_D_obs                     h*ng/mL/mg              26.4314 
AUC_%Extrap_obs                           %               2.8305 
Vz_F_obs                                  L            1671.5792 
Page 113 of 331


Cl _ F _ o b s                                L/ h              3 7. 8 3 3 7  
A U CI N F _ pr e d                         h* n g/ m L           1 1 8 6 3. 9 4 5 2  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              2 6. 3 6 4 3  
A U C _ % E xtr a p _ pr e d                          %               2. 5 8 3 2  
V z _ F _ pr e d                                 L            1 6 7 5. 8 3 4 9  
Cl _ F _ pr e d                               L/ h              3 7. 9 3 0 0  
A U M Cl a st                          h* h* n g/ m L          5 4 1 3 6 4. 5 9 9 6  
A U M CI N F _ o b s                       h* h* n g/ m L          6 1 2 7 9 9. 7 3 5 6  
A U M C _ % E xtr a p _ o b s                          %              1 1. 6 5 7 2  
A U M CI N F _ pr e d                      h* h* n g/ m L          6 0 6 3 9 0. 8 9 3 3  
A U M C _ % E xtr a p _ pr e d                         %              1 0. 7 2 3 5  
M R Tl a st                                   h              4 6. 8 4 1 1  
M R TI N F _ o b s                                h              5 1. 5 2 1 1  
M R TI N F _ pr e d                               h              5 1. 1 1 2 1  
A U C 0 _ 2 4                             h* n g/ m L            3 6 7 9. 1 0 6 3  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 1, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 1  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 3 3        1 1. 1 0                            1. 5 7 2      1. 6 2 5  
      1. 5 0 0        2 6. 9 0                            1 0. 4 4      1 3. 7 2  
      2. 0 1 7        3 4. 2 0                            2 6. 2 2      4 1. 9 6  
      3. 0 0 0        1 6 7. 0                            1 2 5. 1      3 2 2. 2  
      4. 0 0 0        1 5 4. 0                            2 8 5. 6      8 8 2. 6  
      6. 0 0 0        2 3 0. 0                            6 6 9. 6      2 8 7 9.  
      8. 0 0 0        2 5 5. 0                            1 1 5 5.      6 2 9 9.  
      1 2. 0 0        2 9 1. 0                            2 2 4 7. 1. 7 3 6 e + 0 0 4  
      1 6. 0 0        2 9 8. 0                            3 4 2 5. 3. 3 8 8 e + 0 0 4  
      2 4. 0 3        3 1 2. 0                            5 8 7 5. 8. 3 1 5 e + 0 0 4  
      3 6 . 0 0 *      2 6 0. 0      2 6 5. 8     -5. 8 0 0      9 2 8 8. 1. 8 5 0 e + 0 0 5      1. 0 0 0  
      4 8. 0 0 *      2 1 4. 0      2 0 1. 5      1 2. 5 2 1. 2 1 2 e + 0 0 4 3. 0 3 5 e + 0 0 5      1. 0 0 0  
      6 0. 0 0 *      1 4 4. 0      1 5 2. 7     -8. 7 2 6 1. 4 2 4 e + 0 0 4 4. 1 7 2 e + 0 0 5      1. 0 0 0  
      7 2. 0 0 *      1 1 7. 0      1 1 5. 8      1. 2 3 1 1. 5 8 0 e + 0 0 4 5. 1 9 8 e + 0 0 5      1. 0 0 0  
      9 6. 0 0 *      6 2. 6 0      6 6. 5 2     -3. 9 2 0 1. 7 8 9 e + 0 0 4 6. 9 2 6 e + 0 0 5      1. 0 0 0  
      1 2 0. 3 *      4 3. 6 0      3 7. 9 9      5. 6 1 3 1. 9 1 7 e + 0 0 4 8. 2 9 5 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      2 0. 9 0      2 1. 9 6     -1. 0 6 2 1. 9 9 0 e + 0 0 4 9. 2 5 2 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      1 2. 4 0      1 2. 6 2    -0. 2 1 8 9 2. 0 2 9 e + 0 0 4 9. 8 5 8 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Pa ge 1 1 4 of 3 3 1
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Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 6 1  
R s q _ a dj u st e d                                              0. 9 9 5 4  
C orr _ X Y                                                  -0. 9 9 8 0  
N o _ p oi nt s _l a m b d a _ z                                        8  
L a m b d a _ z                                1/ h               0. 0 2 3 1  
L a m b d a _ z _l o w er                            h              3 6. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 0. 0 2 2 7  
Tl a g                                      h               0. 7 5 0 0  
T m a x                                      h              2 4. 0 3 3 3  
C m a x                                  n g/ m L             3 1 2. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 6 9 3 3  
Tl a st                                      h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L              1 2. 4 0 0 0  
A U Cl a st                             h* n g/ m L           2 0 2 8 9. 2 6 5 3  
A U C all                              h* n g/ m L           2 0 2 8 9. 2 6 5 3  
A U CI N F _ o b s                          h* n g/ m L           2 0 8 2 6. 3 5 3 5  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              4 6. 2 8 0 8  
A U C _ % E xtr a p _ o b s                           %               2. 5 7 8 9  
V z _ F _ o b s                                  L             9 3 5. 8 8 6 5  
Cl _ F _ o b s                                L/ h              2 1. 6 0 7 2  
A U CI N F _ pr e d                         h* n g/ m L           2 0 8 3 5. 8 3 6 9  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              4 6. 3 0 1 9  
A U C _ % E xtr a p _ pr e d                          %               2. 6 2 3 2  
V z _ F _ pr e d                                 L             9 3 5. 4 6 0 6  
Cl _ F _ pr e d                               L/ h              2 1. 5 9 7 4  
A U M Cl a st                          h* h* n g/ m L          9 8 5 8 0 2. 1 8 7 1  
A U M CI N F _ o b s                       h* h* n g/ m L         1 0 9 9 2 9 6. 2 0 8 2  
A U M C _ % E xtr a p _ o b s                          %              1 0. 3 2 4 2  
A U M CI N F _ pr e d                      h* h* n g/ m L         1 1 0 1 3 0 0. 1 8 5 5  
A U M C _ % E xtr a p _ pr e d                         %              1 0. 4 8 7 4  
M R Tl a st                                    h              4 8. 5 8 7 4  
M R TI N F _ o b s                                h              5 2. 7 8 3 9  
M R TI N F _ pr e d                               h              5 2. 8 5 6 1  
A U C 0 _ 2 4                             h* n g/ m L            5 8 6 4. 3 2 6 5  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D =
, A P E RI O D = 2, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3 
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 4  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0        7. 2 9 0                           0. 9 1 1 3     0. 4 5 5 6  
     0. 7 5 0 0        1 6. 0 0                            3. 8 2 3      2. 4 1 1  
      1. 0 0 0        2 1. 9 0                            8. 5 6 0      6. 6 4 9  
Pa ge 1 1 5 of 3 3 1
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      1. 5 0 0        3 9. 4 0                            2 3. 8 9      2 6. 9 0  
      2. 0 0 0        6 9. 9 0                            5 1. 2 1      7 6. 6 2  
      3. 0 0 0        9 7. 1 0                            1 3 4. 7      2 9 2. 2  
      4. 0 0 0        1 9 5. 0                            2 8 0. 8      8 2 7. 8  
      6. 0 0 0        3 4 3. 0                            8 1 8. 8      3 6 6 6.  
      8. 0 0 0        3 6 3. 0                            1 5 2 5.      8 6 2 8.  
      1 2. 0 0        3 0 1. 0                            2 8 4 9. 2. 1 7 9 e + 0 0 4  
      1 6. 0 0        2 7 8. 0                            4 0 0 6. 3. 7 9 6 e + 0 0 4  
      2 4. 0 0 *      2 7 3. 0      2 8 6. 3     -1 3. 3 4      6 2 1 0. 8. 2 0 1 e + 0 0 4      1. 0 0 0  
      3 6. 0 0 *      2 2 9. 0      2 3 1. 6     -2. 6 4 2      9 2 1 4. 1. 7 1 6 e + 0 0 5      1. 0 0 0  
      4 8. 0 0 *      1 9 3. 0      1 8 7. 4      5. 6 0 7 1. 1 7 4 e + 0 0 4 2. 7 7 3 e + 0 0 5      1. 0 0 0  
      6 0. 0 0 *      1 4 9. 0      1 5 1. 6     -2. 5 9 6 1. 3 7 8 e + 0 0 4 3. 8 6 9 e + 0 0 5      1. 0 0 0  
      7 2. 0 0 *      1 3 0. 0      1 2 2. 6      7. 3 6 3 1. 5 4 5 e + 0 0 4 4. 9 7 0 e + 0 0 5      1. 0 0 0  
      9 6. 0 0 *      7 8. 7 0      8 0. 2 6     -1. 5 5 9 1. 7 9 1 e + 0 0 4 7. 0 0 6 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      5 3. 0 0      5 2. 5 2     0. 4 7 5 2 1. 9 4 7 e + 0 0 4 8. 6 7 9 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      3 7. 5 0      3 4. 3 6      3. 1 3 6 2. 0 5 4 e + 0 0 4 1. 0 0 9 e + 0 0 6      1. 0 0 0  
      1 6 8. 0 *      2 0. 6 0      2 2. 5 0     -1. 8 9 6 2. 1 2 2 e + 0 0 4 1. 1 1 4 e + 0 0 6      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 6 4  
R s q _ a d j u st e d                                              0. 9 9 5 8 
C orr _ X Y                                                  -0. 9 9 8 2  
N o _ p oi nt s _l a m b d a _ z                                        9  
L a m b d a _ z                                1/ h               0. 0 1 7 7  
L a m b d a _ z _l o w er                            h              2 4. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 9. 2 3 7 2  
Tl a g                                      h               0. 2 5 0 0  
T m a x                                      h               8. 0 0 0 0  
C m a x                                  n g/ m L             3 6 3. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 8 0 6 7  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L              2 0. 6 0 0 0  
A U Cl a st                             h* n g/ m L           2 1 2 1 8. 2 7 3 6  
A U C all                              h* n g/ m L           2 1 2 1 8. 2 7 3 6  
A U CI N F _ o b s                          h* n g/ m L           2 2 3 8 4. 3 8 5 1  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              4 9. 7 4 3 1  
A U C _ % E xtr a p _ o b s                           %               5. 2 0 9 5  
V z _ F _ o b s                                  L            1 1 3 7. 9 9 4 6  
Cl _ F _ o b s                                L/ h              2 0. 1 0 3 3  
A U CI N F _ pr e d                         h* n g/ m L           2 2 4 9 1. 7 1 5 5  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              4 9. 9 8 1 6  
A U C _ % E xtr a p _ pr e d                          %               5. 6 6 1 8  
V z _ F _ pr e d                                 L            1 1 3 2. 5 6 4 1  
Cl _ F _ pr e d                               L/ h              2 0. 0 0 7 4  
A U M Cl a st                          h* h* n g/ m L         1 1 1 3 9 4 4. 4 4 9 4  
A U M CI N F _ o b s                       h* h* n g/ m L         1 3 7 5 8 6 1. 6 6 8 0  
A U M C _ % E xtr a p _ o b s                          %              1 9. 0 3 6 6  
A U M CI N F _ pr e d                      h* h* n g/ m L         1 3 9 9 9 6 8. 8 6 0 4  
A U M C _ % E xtr a p _ pr e d                         %              2 0. 4 3 0 8  
M R Tl a st                                   h              5 2. 4 9 9 3  
M R TI N F _ o b s                                h              6 1. 4 6 5 2  
M R TI N F _ pr e d                               h              6 2. 2 4 3 8  
A U C 0 _ 2 4                             h* n g/ m L            6 2 1 0. 2 2 1 7  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 2, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 3  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
Pa ge 1 1 6 of 3 3 1
PI
PI


Settings 
-------- 
Model:  Plasma Data, Extravascular Administration 
Number of nonmissing observations:   22 
Dose time:      0.00 
Dose amount:      450.00 
Calculation method:  Linear Trapezoidal Rule for for Increasing Values, 
                     Log Trapezoidal Rule for Decreasing Values 
Weighting for lambda_z calculations:  Uniform weighting 
Lambda_z method:  Find best fit for lambda_z,  Log regression 
 
 
Summary Table 
------------- 
      Time         Conc.      Pred.    Residual      AUC       AUMC      Weight 
          h       ng/mL       ng/mL       ng/mL     h*ng/mL   h*h*ng/mL 
------------------------------------------------------------------------------- 
     0.0000       0.0000                           0.0000     0.0000 
     0.2500       0.0000                           0.0000     0.0000 
     0.5333       0.0000                           0.0000     0.0000 
     0.7500       0.0000                           0.0000     0.0000 
      1.000       0.0000                           0.0000     0.0000 
      1.500        6.710                            1.678      2.516 
      2.000        10.10                            5.880      10.08 
      3.000        39.80                            30.83      79.88 
      4.000        66.40                            83.93      272.4 
      6.000        123.0                            273.3      1276. 
      8.000        169.0                            565.3      3366. 
      12.00        221.0                            1345. 1.137e+004 
      16.00        211.0                            2209. 2.345e+004 
      24.02        203.0                            3868. 5.661e+004 
      36.00 *      185.0      180.4      4.631      6192. 1.261e+005      1.000 
      48.00 *      149.0      138.9      10.15      8188. 2.095e+005      1.000 
      60.02 *      97.80      106.9     -9.052      9649. 2.878e+005      1.000 
      72.00 *      85.40      82.29      3.113 1.075e+004 3.600e+005      1.000 
      96.00 *      46.40      48.76     -2.365 1.228e+004 4.870e+005      1.000 
      120.0 *      28.90      28.90  0.0009656 1.317e+004 5.820e+005      1.000 
      144.0 *      15.60      17.13     -1.526 1.368e+004 6.497e+005      1.000 
      168.0 *      11.20      10.15      1.051 1.400e+004 6.992e+005      1.000 
 
 
*) Starred values were included in the estimation of Lambda_z. 
 
 
Final Parameters 
--------------- 
Rsq                                                       0.9953 
Rsq_adjusted                                              0.9945 
Corr_XY                                                  -0.9976 
No_points_lambda_z                                        8 
Lambda_z                                1/h               0.0218 
Lambda_z_lower                            h              36.0000 
Lambda_z_upper                            h             168.0000 
HL_Lambda_z                               h              31.7958 
Tlag                                      h               1.0000 
Tmax                                      h              12.0000 
Cmax                                  ng/mL             221.0000 
Cmax_D                             ng/mL/mg               0.4911 
Tlast                                     h             168.0000 
Clast                                 ng/mL              11.2000 
AUClast                             h*ng/mL           14002.8523 
AUCall                              h*ng/mL           14002.8523 
AUCINF_obs                          h*ng/mL           14516.6142 
AUCINF_D_obs                     h*ng/mL/mg              32.2591 
AUC_%Extrap_obs                           %               3.5391 
Vz_F_obs                                  L            1421.9719 
Cl_F_obs                                L/h              30.9990 
AUCINF_pred                         h*ng/mL           14468.4189 
AUCINF_D_pred                    h*ng/mL/mg              32.1520 
AUC_%Extrap_pred                          %               3.2178 
Vz_F_pred                                 L            1426.7086 
Cl_F_pred                               L/h              31.1022 
AUMClast                          h*h*ng/mL          699220.4135 
Page 117 of 331


A U M CI N F _ o b s                       h* h* n g/ m L          8 0 9 0 9 9. 4 8 1 4  
A U M C _ % E xtr a p _ o b s                          %              1 3. 5 8 0 4  
A U M CI N F _ pr e d                      h* h* n g/ m L          7 9 8 7 9 1. 8 7 3 6  
A U M C _ % E xtr a p _ pr e d                         %              1 2. 4 6 5 3  
M R Tl a st                                    h              4 9. 9 3 4 1  
M R TI N F _ o b s                                h              5 5. 7 3 6 1  
M R TI N F _ pr e d                               h              5 5. 2 0 9 3  
A U C 0 _ 2 4                             h* n g/ m L            3 8 6 5. 0 3 5 6  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 2, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 4  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      2. 0 0 0        8. 6 9 0                            2. 1 7 3      4. 3 4 5  
      3. 0 0 0        1 5. 4 0                            1 4. 2 2      3 6. 1 4  
      4. 0 0 0        3 7. 3 0                            4 0. 5 7      1 3 3. 8  
      6. 0 0 0        1 6 4. 0                            2 4 1. 9      1 2 6 7.  
      8. 0 0 0        1 7 6. 0                            5 8 1. 9      3 6 5 9.  
      1 2. 0 0        2 1 7. 0                            1 3 6 8. 1. 1 6 8 e + 0 0 4  
      1 6. 0 0        2 2 6. 0                            2 2 5 4. 2. 4 1 2 e + 0 0 4  
      2 4. 0 0        1 9 4. 0                            3 9 3 1. 5. 7 4 9 e + 0 0 4  
      3 6. 0 0        1 1 7. 0                            5 7 5 8. 1. 1 1 4 e + 0 0 5  
      4 8. 0 0        1 0 6. 0                            7 0 9 5. 1. 6 7 4 e + 0 0 5  
      6 0. 0 0        8 0. 6 0                            8 2 0 7. 2. 2 7 2 e + 0 0 5  
      7 2. 0 0        5 3. 6 0                            9 0 0 2. 2. 7 9 3 e + 0 0 5  
      9 6. 0 0 *      4 2. 2 0      4 0. 7 8      1. 4 1 5 1. 0 1 5 e + 0 0 4 3. 7 4 8 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      2 1. 7 0      2 3. 2 4     -1. 5 3 5 1. 0 8 9 e + 0 0 4 4. 5 3 8 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      1 3. 7 0      1 3. 2 4     0. 4 6 3 1 1. 1 3 0 e + 0 0 4 5. 0 8 5 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      7. 5 4 0      7. 5 4 1  -0. 0 0 1 0 4 7 1. 1 5 5 e + 0 0 4 5. 4 6 8 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 5 6  
R s q _ a dj u st e d                                              0. 9 9 3 4  
C orr _ X Y                                                  -0. 9 9 7 8  
N o _ p oi nt s _l a m b d a _ z                                        4  
L a m b d a _ z                                1/ h               0. 0 2 3 4  
Pa ge 1 1 8 of 3 3 1
PI
PI


L a m b d a _ z _l o w er                            h              9 6. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              2 9. 5 6 6 3  
Tl a g                                      h               1. 5 0 0 0  
T m a x                                      h              1 6. 0 0 0 0  
C m a x                                  n g/ m L             2 2 6. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 5 0 2 2  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L               7. 5 4 0 0  
A U Cl a st                             h* n g/ m L           1 1 5 5 0. 5 3 5 3  
A U C all                              h* n g/ m L           1 1 5 5 0. 5 3 5 3  
A U CI N F _ o b s                          h* n g/ m L           1 1 8 7 2. 1 5 5 6  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              2 6. 3 8 2 6  
A U C _ % E xtr a p _ o b s                           %               2. 7 0 9 0  
V z _ F _ o b s                                  L            1 6 1 6. 7 9 5 3  
Cl _ F _ o b s                                L/ h              3 7. 9 0 3 8  
A U CI N F _ pr e d                         h* n g/ m L           1 1 8 7 2. 2 0 0 3  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              2 6. 3 8 2 7  
A U C _ % E xtr a p _ pr e d                          %               2. 7 0 9 4  
V z _ F _ pr e d                                 L            1 6 1 6. 7 8 9 2  
Cl _ F _ pr e d                               L/ h              3 7. 9 0 3 7  
A U M Cl a st                          h* h* n g/ m L          5 4 6 8 0 1. 8 5 6 8  
A U M CI N F _ o b s                       h* h* n g/ m L          6 1 4 5 5 2. 8 4 8 9  
A U M C _ % E xtr a p _ o b s                          %              1 1. 0 2 4 4  
A U M CI N F _ pr e d                      h* h* n g/ m L          6 1 4 5 6 2. 2 5 7 5  
A U M C _ % E xtr a p _ pr e d                         %              1 1. 0 2 5 8  
M R Tl a st                                   h              4 7. 3 4 0 0  
M R TI N F _ o b s                                h              5 1. 7 6 4 2  
M R TI N F _ pr e d                               h              5 1. 7 6 4 8  
A U C 0 _ 2 4                             h* n g/ m L            3 9 3 0. 6 1 1 7  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 1, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 4  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      2. 0 0 0        1 6. 2 0                            4. 0 5 0      8. 1 0 0  
      3. 0 0 0        2 7. 6 0                            2 5. 9 5      6 5. 7 0  
      4. 0 0 0        5 7. 3 0                            6 8. 4 0      2 2 1. 7  
      6. 0 0 0        1 0 9. 0                            2 3 4. 7      1 1 0 5.  
      8. 0 0 0        1 6 4. 0                            5 0 7. 7      3 0 7 1.  
      1 2. 0 0        2 1 5. 0                            1 2 6 6. 1. 0 8 5 e + 0 0 4  
Pa ge 1 1 9 of 3 3 1
PI
PI


      1 6. 0 0        2 2 3. 0                            2 1 4 2. 2. 3 1 5 e + 0 0 4  
      2 4. 0 0        2 7 2. 0                            4 1 2 2. 6. 3 5 3 e + 0 0 4  
      3 6. 0 0 *      2 3 4. 0      2 2 5. 3      8. 7 3 5      7 1 5 2. 1. 5 4 0 e + 0 0 5      1. 0 0 0  
      4 8. 0 0 *      1 7 2. 0      1 7 4. 1     -2. 0 5 3      9 5 6 9. 2. 5 4 8 e + 0 0 5      1. 0 0 0  
      6 0. 0 0 *      1 3 1. 0      1 3 4. 5     -3. 4 8 4 1. 1 3 8 e + 0 0 4 3. 5 1 8 e + 0 0 5      1. 0 0 0  
      7 2. 0 0 *      1 1 0. 0      1 0 3. 9      6. 0 8 9 1. 2 8 2 e + 0 0 4 4. 4 6 8 e + 0 0 5      1. 0 0 0  
      9 6. 0 0 *      5 6. 2 0      6 2. 0 4     -5. 8 3 5 1. 4 7 4 e + 0 0 4 6. 0 5 7 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      3 8. 8 0      3 7. 0 4      1. 7 6 5 1. 5 8 7 e + 0 0 4 7. 2 6 6 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      2 0. 9 0      2 2. 1 1     -1. 2 1 0 1. 6 5 6 e + 0 0 4 8. 1 7 4 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      1 3. 9 0      1 3. 2 0     0. 7 0 0 0 1. 6 9 7 e + 0 0 4 8. 8 1 3 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 6 8  
R s q _ a dj u st e d                                              0. 9 9 6 3  
C orr _ X Y                                                  -0. 9 9 8 4  
N o _ p oi nt s _l a m b d a _ z                                        8  
L a m b d a _ z                                1/ h               0. 0 2 1 5  
L a m b d a _ z _l o w er                            h              3 6. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 2. 2 5 0 1  
Tl a g                                      h               1. 5 0 0 0  
T m a x                                      h              2 4. 0 0 0 0  
C m a x                                  n g/ m L             2 7 2. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 6 0 4 4  
Tl a st                                      h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L              1 3. 9 0 0 0  
A U Cl a st                             h* n g/ m L           1 6 9 7 4. 2 2 1 7  
A U C all                              h* n g/ m L           1 6 9 7 4. 2 2 1 7  
A U CI N F _ o b s                           h* n g/ m L           1 7 6 2 0. 9 4 8 5  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              3 9. 1 5 7 7  
A U C _ % E xtr a p _ o b s                           %               3. 6 7 0 2  
V z _ F _ o b s                                  L            1 1 8 8. 1 9 9 4  
Cl _ F _ o b s                                L/ h              2 5. 5 3 7 8  
A U CI N F _ pr e d                         h* n g/ m L           1 7 5 8 8. 3 8 1 6  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              3 9. 0 8 5 3  
A U C _ % E xtr a p _ pr e d                          %               3. 4 9 1 8  
V z _ F _ pr e d                                 L            1 1 9 0. 3 9 9 5  
Cl _ F _ pr e d                               L/ h              2 5. 5 8 5 1  
A U M Cl a st                          h* h* n g/ m L          8 8 1 3 4 4. 2 5 4 3  
A U M CI N F _ o b s                       h* h* n g/ m L         1 0 2 0 0 8 4. 6 9 4 3  
A U M C _ % E xtr a p _ o b s                          %              1 3. 6 0 0 9  
A U M CI N F _ pr e d                      h* h* n g/ m L         1 0 1 3 0 9 8. 1 9 9 9  
A U M C _ % E xtr a p _ pr e d                         %              1 3. 0 0 5 1  
M R Tl a st                                    h              5 1. 9 2 2 5  
M R TI N F _ o b s                                h              5 7. 8 9 0 5  
M R TI N F _ pr e d                               h              5 7. 6 0 0 4  
A U C 0 _ 2 4                             h* n g/ m L            4 1 2 1. 7 0 0 0  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 1, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 2  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
Pa ge 1 2 0 of 3 3 1
PI
PI


                     Log Trapezoidal Rule for Decreasing Values 
Weighting for lambda_z calculations:  Uniform weighting 
Lambda_z method:  Find best fit for lambda_z,  Log regression 
 
 
Summary Table 
------------- 
      Time         Conc.      Pred.    Residual      AUC       AUMC      Weight 
          h       ng/mL       ng/mL       ng/mL     h*ng/mL   h*h*ng/mL 
------------------------------------------------------------------------------- 
     0.0000       0.0000                           0.0000     0.0000 
     0.2500       0.0000                           0.0000     0.0000 
     0.5000       0.0000                           0.0000     0.0000 
     0.7500       0.0000                           0.0000     0.0000 
      1.033       0.0000                           0.0000     0.0000 
      1.500        8.070                            1.883      2.825 
      2.000        23.20                            9.701      17.45 
      3.000        76.30                            59.45      155.1 
      4.000        97.80                            146.5      465.2 
      6.000        183.0                            427.3      1954. 
      8.000        181.0                            791.3      4502. 
      12.00        210.0                            1573. 1.244e+004 
      16.00        195.0                            2383. 2.375e+004 
      24.00        180.0                            3882. 5.366e+004 
      36.00 *      149.0      158.9     -9.872      5850. 1.123e+005      1.000 
      48.00 *      130.0      122.3      7.701      7522. 1.823e+005      1.000 
      60.00 *      93.20      94.15    -0.9451      8849. 2.535e+005      1.000 
      72.00 *      76.00      72.47      3.528      9860. 3.201e+005      1.000 
      96.00 *      44.60      42.95      1.654 1.127e+004 4.373e+005      1.000 
      120.0 *      24.30      25.45     -1.149 1.208e+004 5.230e+005      1.000 
      144.0 *      13.40      15.08     -1.681 1.252e+004 5.805e+005      1.000 
      168.0 *      9.800      8.937     0.8634 1.279e+004 6.234e+005      1.000 
 
 
*) Starred values were included in the estimation of Lambda_z. 
 
 
Final Parameters 
--------------- 
Rsq                                                       0.9952 
Rsq_adjusted                                              0.9944 
Corr_XY                                                  -0.9976 
No_points_lambda_z                                        8 
Lambda_z                                1/h               0.0218 
Lambda_z_lower                            h              36.0000 
Lambda_z_upper                            h             168.0000 
HL_Lambda_z                               h              31.7920 
Tlag                                      h               1.0333 
Tmax                                      h              12.0000 
Cmax                                  ng/mL             210.0000 
Cmax_D                             ng/mL/mg               0.4667 
Tlast                                     h             168.0000 
Clast                                 ng/mL               9.8000 
AUClast                             h*ng/mL           12792.1802 
AUCall                              h*ng/mL           12792.1802 
AUCINF_obs                          h*ng/mL           13241.6680 
AUCINF_D_obs                     h*ng/mL/mg              29.4259 
AUC_%Extrap_obs                           %               3.3945 
Vz_F_obs                                  L            1558.6967 
Cl_F_obs                                L/h              33.9836 
AUCINF_pred                         h*ng/mL           13202.0677 
AUCINF_D_pred                    h*ng/mL/mg              29.3379 
AUC_%Extrap_pred                          %               3.1047 
Vz_F_pred                                 L            1563.3721 
Cl_F_pred                               L/h              34.0856 
AUMClast                          h*h*ng/mL          623428.2992 
AUMCINF_obs                       h*h*ng/mL          719558.4925 
AUMC_%Extrap_obs                          %              13.3596 
AUMCINF_pred                      h*h*ng/mL          711089.3351 
AUMC_%Extrap_pred                         %              12.3277 
MRTlast                                   h              48.7351 
MRTINF_obs                                h              54.3405 
MRTINF_pred                               h              53.8620 
Page 121 of 331


A U C 0 _ 2 4                             h* n g/ m L            3 8 8 2. 1 2 6 0  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D =
, A P E RI O D = 1, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3 
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 3  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0        7. 0 6 0                           0. 8 8 2 5     0. 4 4 1 3  
     0. 7 5 0 0        1 7. 2 0                            3. 9 1 5      2. 4 9 5  
      1. 0 0 0        2 5. 5 0                            9. 2 5 3      7. 2 9 5  
      1. 5 0 0        3 8. 3 0                            2 5. 2 0      2 8. 0 3  
      2. 0 0 0        3 9. 4 0                            4 4. 6 3      6 2. 1 0  
      3. 0 0 0        6 7. 2 0                            9 7. 9 3      2 0 2. 3  
      4. 0 0 0        1 0 9. 0                            1 8 6. 0      5 2 1. 1  
      6. 0 0 0        1 7 3. 0                            4 6 8. 0      1 9 9 5.  
      8. 0 0 0        2 1 8. 0                            8 5 9. 0      4 7 7 7.  
      1 2. 0 0        2 2 7. 0                            1 7 4 9. 1. 3 7 1 e + 0 0 4  
      1 6. 0 0        2 3 7. 0                            2 6 7 7. 2. 6 7 5 e + 0 0 4  
      2 4. 0 0        2 9 0. 0                            4 7 8 5. 6. 9 7 5 e + 0 0 4  
      3 6. 0 0        2 6 7. 0                            8 1 2 5. 1. 6 9 7 e + 0 0 5  
      4 8. 0 0        2 3 4. 0                       1. 1 1 3 e + 0 0 4 2. 9 5 4 e + 0 0 5  
      6 0. 0 0 *      1 9 5. 0      1 9 9. 7     -4. 6 8 6 1. 3 6 9 e + 0 0 4 4. 3 3 5 e + 0 0 5      1. 0 0 0  
      7 2. 0 0 *      1 6 6. 0      1 5 9. 4      6. 5 8 1 1. 5 8 6 e + 0 0 4 5. 7 5 8 e + 0 0 5      1. 0 0 0  
      9 6. 0 0 *      1 0 0. 0      1 0 1. 6     -1. 6 0 8 1. 8 9 8 e + 0 0 4 8. 3 5 2 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      6 5. 8 0      6 4. 7 6      1. 0 3 9 2. 0 9 4 e + 0 0 4 1. 0 4 5 e + 0 0 6      1. 0 0 0  
      1 4 4. 0 *      3 9. 7 0      4 1. 2 8     -1. 5 7 6 2. 2 1 8 e + 0 0 4 1. 2 0 8 e + 0 0 6      1. 0 0 0  
      1 6 8. 0 *      2 6. 9 0      2 6. 3 1     0. 5 9 2 2 2. 2 9 7 e + 0 0 4 1. 3 3 0 e + 0 0 6      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 8 5  
R s q _ a dj u st e d                                              0. 9 9 8 1  
C orr _ X Y                                                  -0. 9 9 9 2  
N o _ p oi nt s _l a m b d a _ z                                        6  
L a m b d a _ z                                1/ h               0. 0 1 8 8  
L a m b d a _ z _l o w er                            h              6 0. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 6. 9 3 3 6  
Tl a g                                      h               0. 2 5 0 0  
T m a x                                      h              2 4. 0 0 0 0  
C m a x                                  n g/ m L             2 9 0. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 6 4 4 4  
Pa ge 1 2 2 of 3 3 1
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Tl a st                                      h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L              2 6. 9 0 0 0  
A U Cl a st                             h* n g/ m L           2 2 9 7 0. 4 3 7 5  
A U C all                              h* n g/ m L           2 2 9 7 0. 4 3 7 5  
A U CI N F _ o b s                           h* n g/ m L           2 4 4 0 3. 7 7 3 9  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              5 4. 2 3 0 6  
A U C _ % E xtr a p _ o b s                           %               5. 8 7 3 4  
V z _ F _ o b s                                  L             9 8 2. 5 4 2 6  
Cl _ F _ o b s                                L/ h              1 8. 4 3 9 8  
A U CI N F _ pr e d                         h* n g/ m L           2 4 3 7 2. 2 2 0 7  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              5 4. 1 6 0 5  
A U C _ % E xtr a p _ pr e d                          %               5. 7 5 1 6  
V z _ F _ pr e d                                 L             9 8 3. 8 1 4 6  
Cl _ F _ pr e d                               L/ h              1 8. 4 6 3 6  
A U M Cl a st                          h* h* n g/ m L         1 3 3 0 2 4 2. 4 5 5 6  
A U M CI N F _ o b s                       h* h* n g/ m L         1 6 4 7 4 1 6. 7 1 1 0  
A U M C _ % E xtr a p _ o b s                          %              1 9. 2 5 2 8  
A U M CI N F _ pr e d                      h* h* n g/ m L         1 6 4 0 4 3 4. 4 9 4 3  
A U M C _ % E xtr a p _ pr e d                         %              1 8. 9 0 9 1  
M R Tl a st                                   h              5 7. 9 1 1 1  
M R TI N F _ o b s                                h              6 7. 5 0 6 6  
M R TI N F _ pr e d                               h              6 7. 3 0 7 6  
A U C 0 _ 2 4                             h* n g/ m L            4 7 8 5. 0 2 7 5  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 2 , T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3 
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 2  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                            0. 0 0 0 0     0. 0 0 0 0  
     0. 2 6 6 7       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 1 7       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0        1 4. 2 0                            3. 4 3 2      5. 1 4 7  
      2. 0 0 0        3 8. 3 0                            1 6. 5 6      2 9. 6 2  
      3. 0 0 0        7 3. 9 0                            7 2. 6 6      1 7 8. 8  
      4. 0 0 0        1 2 9. 0                            1 7 4. 1      5 4 7. 6  
      6. 0 0 0        2 3 3. 0                            5 3 6. 1      2 4 6 2.  
      8. 0 0 0        2 7 4. 0                            1 0 4 3.      6 0 5 2.  
      1 2. 0 0        2 9 7. 0                            2 1 8 5. 1. 7 5 6 e + 0 0 4  
      1 6. 0 0        2 9 0. 0                            3 3 5 9. 3. 3 9 9 e + 0 0 4  
      2 4. 0 0        2 9 9. 0                            5 7 1 5. 8. 1 2 5 e + 0 0 4  
      3 6. 0 0        2 6 8. 0                            9 1 1 4. 1. 8 2 8 e + 0 0 5  
      4 8. 0 0        2 2 3. 0                       1. 2 0 5 e + 0 0 4 3. 0 5 7 e + 0 0 5  
      6 0. 0 0        1 7 0. 0                       1. 4 4 0 e + 0 0 4 4. 3 1 6 e + 0 0 5  
      7 2. 7 3        1 2 5. 0                       1. 6 2 6 e + 0 0 4 5. 5 4 7 e + 0 0 5  
      9 6. 0 3        8 1. 8 0                       1. 8 6 3 e + 0 0 4 7. 5 3 0 e + 0 0 5  
Pa ge 1 2 3 of 3 3 1
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      1 2 0. 0 *      4 2. 5 0      4 2. 2 1     0. 2 9 2 0 2. 0 0 7 e + 0 0 4 9. 0 6 5 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      2 4. 4 0      2 4. 7 4    -0. 3 3 8 7 2. 0 8 5 e + 0 0 4 1. 0 0 9 e + 0 0 6      1. 0 0 0  
      1 6 8. 0 *      1 4. 6 0      1 4. 5 0     0. 1 0 0 3 2. 1 3 1 e + 0 0 4 1. 0 8 0 e + 0 0 6      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 9 5  
R s q _ a dj u st e d                                              0. 9 9 9 0  
C orr _ X Y                                                  - 0. 9 9 9 8  
N o _ p oi nt s _l a m b d a _ z                                        3  
L a m b d a _ z                                1/ h               0. 0 2 2 3  
L a m b d a _ z _l o w er                            h             1 2 0. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 1. 1 3 8 6  
Tl a g                                      h               1. 0 1 6 7  
T m a x                                      h              2 4. 0 0 0 0  
C m a x                                  n g/ m L             2 9 9. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 6 6 4 4  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L              1 4. 6 0 0 0  
A U Cl a st                             h* n g/ m L           2 1 3 1 1. 5 8 2 2  
A U C all                              h* n g/ m L           2 1 3 1 1. 5 8 2 2  
A U CI N F _ o b s                          h* n g/ m L           2 1 9 6 7. 4 6 5 6  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              4 8. 8 1 6 6  
A U C _ % E xtr a p _ o b s                           %               2. 9 8 5 7  
V z _ F _ o b s                                  L             9 2 0. 2 5 1 1  
Cl _ F _ o b s                                L/ h              2 0. 4 8 4 8  
A U CI N F _ pr e d                         h* n g/ m L           2 1 9 6 2. 9 6 0 0  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              4 8. 8 0 6 6  
A U C _ % E xtr a p _ pr e d                          %               2. 9 6 5 8  
V z _ F _ pr e d                                 L             9 2 0. 4 3 9 9  
Cl _ F _ pr e d                               L/ h              2 0. 4 8 9 0  
A U M Cl a st                          h* h* n g/ m L         1 0 7 9 9 8 7. 9 7 6 3  
A U M CI N F _ o b s                       h* h* n g/ m L         1 2 1 9 6 4 0. 9 8 7 1  
A U M C _ % E xtr a p _ o b s                          %              1 1. 4 5 0 3  
A U M CI N F _ pr e d                      h* h* n g/ m L         1 2 1 8 6 8 1. 6 3 8 0  
A U M C _ % E xtr a p _ pr e d                         %              1 1. 3 8 0 6  
M R Tl a st                                   h              5 0. 6 7 6 1  
M R TI N F _ o b s                                h              5 5. 5 2 0 3  
M R TI N F _ pr e d                               h              5 5. 4 8 8 0  
A U C 0 _ 2 4                             h* n g/ m L            5 7 1 5. 0 5 1 0  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 1, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 2  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
Pa ge 1 2 4 of 3 3 1
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PI


      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g / m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L 
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 3 3 3       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0        1 1. 0 0                            2. 7 5 0      4. 1 2 5  
      2. 0 0 0        2 7. 0 0                            1 2. 2 5      2 1. 7 5  
      3. 0 0 0        7 5. 7 0                            6 3. 6 0      1 6 2. 3  
      4. 0 0 0        1 1 1. 0                            1 5 7. 0      4 9 7. 9  
      6. 0 0 0        1 5 3. 0                            4 2 1. 0      1 8 6 0. 
      8. 0 5 0        1 7 6. 0                            7 5 8. 2      4 2 5 3.  
      1 2. 0 0        2 1 1. 0                            1 5 2 3. 1. 2 0 5 e + 0 0 4  
      1 6. 0 5        2 1 1. 0                            2 3 7 7. 2. 4 0 4 e + 0 0 4  
      2 4. 0 2        2 1 8. 0                            4 0 8 6. 5. 8 3 8 e + 0 0 4  
      3 6. 0 0        1 9 4. 0                            6 5 5 2. 1. 3 2 1 e + 0 0 5  
      4 8. 0 0 *      1 4 9. 0      1 5 1. 1     -2. 1 2 5      8 5 9 8. 2. 1 7 5 e + 0 0 5      1. 0 0 0  
      6 0. 0 0 *      1 0 9. 0      1 0 6. 2      2. 8 0 9 1. 0 1 3 e + 0 0 4 2. 9 9 9 e + 0 0 5      1. 0 0 0  
      7 2. 0 0 *      7 5. 2 0      7 4. 6 2     0. 5 8 3 2 1. 1 2 3 e + 0 0 4 3. 7 1 6 e + 0 0 5      1. 0 0 0  
      9 5. 7 3 *      3 7. 2 0      3 7. 1 3    0. 0 6 8 4 2 1. 2 5 1 e + 0 0 4 4. 7 7 3 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      1 7. 1 0      1 8. 1 9     -1. 0 9 0 1. 3 1 3 e + 0 0 4 5. 4 4 0 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      9. 3 5 0      8. 9 8 1     0. 3 6 8 7 1. 3 4 4 e + 0 0 4 5. 8 4 3 e + 0 0 5      1. 0 0 0  
      1 6 8. 0       0. 0 0 0 0                       1. 3 5 6 e + 0 0 4 6. 0 0 5 e + 0 0 5  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z.  
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 8 9  
R s q _ a dj u st e d                                              0. 9 9 8 7  
C orr _ X Y                                                  -0. 9 9 9 5  
N o _ p oi nt s _l a m b d a _ z                                        6  
L a m b d a _ z                                1/ h               0. 0 2 9 4  
L a m b d a _ z _l o w er                            h              4 8. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 4 4. 0 0 0 0  
H L _ L a m b d a _ z                               h              2 3. 5 7 1 8  
Tl a g                                      h               1. 0 0 0 0  
T m a x                                      h              2 4. 0 1 6 7  
C m a x                                  n g/ m L             2 1 8. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 4 8 4 4  
Tl a st                                     h             1 4 4. 0 0 0 0  
Cl a st                                  n g/ m L               9. 3 5 0 0  
A U Cl a st                             h* n g/ m L           1 3 4 4 3. 0 1 6 3  
A U C all                              h* n g/ m L           1 3 5 5 5. 2 1 6 3  
A U CI N F _ o b s                          h* n g/ m L           1 3 7 6 0. 9 8 0 4  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              3 0. 5 8 0 0  
A U C _ % E xtr a p _ o b s                           %               2. 3 1 0 6  
V z _ F _ o b s                                  L            1 1 1 2. 0 6 3 6  
Cl _ F _ o b s                                L/ h              3 2. 7 0 1 2  
A U CI N F _ pr e d                         h* n g/ m L           1 3 7 4 8. 4 4 2 5  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              3 0. 5 5 2 1  
A U C _ % E xtr a p _ pr e d                          %               2. 2 2 1 5  
V z _ F _ pr e d                                 L            1 1 1 3. 0 7 7 7  
Cl _ F _ pr e d                               L/ h              3 2. 7 3 1 0  
A U M Cl a st                          h* h* n g/ m L          5 8 4 3 4 6. 9 1 8 0  
A U M CI N F _ o b s                       h* h* n g/ m L          6 4 0 9 4 6. 7 0 7 5  
A U M C _ % E xtr a p _ o b s                          %               8. 8 3 0 7  
A U M CI N F _ pr e d                      h* h* n g/ m L          6 3 8 7 1 4. 8 7 9 9  
A U M C _ % E xtr a p _ pr e d                         %               8. 5 1 2 1  
M R Tl a st                                   h              4 3. 4 6 8 4  
M R TI N F _ o b s                                h              4 6. 5 7 7 1  
M R TI N F _ pr e d                               h              4 6. 4 5 7 3  
A U C 0 _ 2 4                             h* n g/ m L            4 0 8 2. 2 6 6 8  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 1, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
Pa ge 1 2 5 of 3 3 1
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                                                  Date:    
 
                                                  Time:     09:23:22 
 
 
                  WINNONLIN NONCOMPARTMENTAL ANALYSIS PROGRAM 
                                   7.0.0.2535 
                            Core Version 04Jun2007 
 
Settings 
-------- 
Model:  Plasma Data, Extravascular Administration 
Number of nonmissing observations:   22 
Dose time:      0.00 
Dose amount:      450.00 
Calculation method:  Linear Trapezoidal Rule for for Increasing Values, 
                     Log Trapezoidal Rule for Decreasing Values 
Weighting for lambda_z calculations:  Uniform weighting 
Lambda_z method:  Find best fit for lambda_z,  Log regression 
 
 
Summary Table 
------------- 
      Time         Conc.      Pred.    Residual      AUC       AUMC      Weight 
          h       ng/mL       ng/mL       ng/mL     h*ng/mL   h*h*ng/mL 
------------------------------------------------------------------------------- 
     0.0000       0.0000                           0.0000     0.0000 
     0.2500       0.0000                           0.0000     0.0000 
     0.5000       0.0000                           0.0000     0.0000 
     0.7500       0.0000                           0.0000     0.0000 
      1.000        11.50                            1.438      1.438 
      1.600        12.20                            8.548      10.74 
      2.217        56.20                            29.64      55.17 
      3.000        133.0                            103.7      260.2 
      4.000        157.0                            248.7      773.7 
      6.000        182.0                            587.7      2494. 
      8.000        190.0                            959.7      5106. 
      12.00        180.0                            1700. 1.249e+004 
      16.00        199.0                            2458. 2.318e+004 
      24.02        207.0                            4085. 5.587e+004 
      36.00        189.0                            6456. 1.268e+005 
      48.02        156.0                            8523. 2.132e+005 
      60.00 *      118.0      115.1      2.939 1.015e+004 3.009e+005      1.000 
      72.00 *      91.80      92.26    -0.4579 1.141e+004 3.832e+005      1.000 
      96.02 *      57.00      59.30     -2.295 1.316e+004 5.289e+005      1.000 
      120.0 *      38.20      38.13    0.06698 1.429e+004 6.496e+005      1.000 
      144.1 *      25.00      24.47     0.5291 1.504e+004 7.481e+005      1.000 
      168.0 *      15.70      15.76   -0.06156 1.551e+004 8.222e+005      1.000 
 
 
*) Starred values were included in the estimation of Lambda_z. 
 
 
Final Parameters 
--------------- 
Rsq                                                       0.9991 
Rsq_adjusted                                              0.9989 
Corr_XY                                                  -0.9995 
No_points_lambda_z                                        6 
Lambda_z                                1/h               0.0184 
Lambda_z_lower                            h              60.0000 
Lambda_z_upper                            h             168.0000 
HL_Lambda_z                               h              37.6580 
Tlag                                      h               0.7500 
Tmax                                      h              24.0167 
Cmax                                  ng/mL             207.0000 
Cmax_D                             ng/mL/mg               0.4600 
Tlast                                     h             168.0000 
Clast                                 ng/mL              15.7000 
AUClast                             h*ng/mL           15514.4277 
AUCall                              h*ng/mL           15514.4277 
AUCINF_obs                          h*ng/mL           16367.3922 
AUCINF_D_obs                     h*ng/mL/mg              36.3720 
AUC_%Extrap_obs                           %               5.2114 
Page 126 of 331
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V z _ F _ o b s                                  L            1 4 9 3. 7 0 3 4  
Cl _ F _ o b s                                L/ h              2 7. 4 9 3 7  
A U CI N F _ pr e d                         h* n g/ m L           1 6 3 7 0. 7 3 6 6  
A U C I N F _ D _ pr e d                    h* n g/ m L/ m g              3 6. 3 7 9 4 
A U C _ % E xtr a p _ pr e d                          %               5. 2 3 0 7  
V z _ F _ pr e d                                 L            1 4 9 3. 3 9 8 2  
Cl _ F _ pr e d                               L/ h              2 7. 4 8 8 1  
A U M Cl a st                          h* h* n g/ m L          8 2 2 2 0 6. 6 8 3 8  
A U M CI N F _ o b s                       h* h* n g/ m L         1 0 1 1 8 4 5. 4 0 0 5  
A U M C _ % E xtr a p _ o b s                          %              1 8. 7 4 1 9  
A U M CI N F _ pr e d                      h* h* n g/ m L         1 0 1 2 5 8 8. 9 4 1 2  
A U M C _ % E xtr a p _ pr e d                         %              1 8. 8 0 1 5  
M R Tl a st                                   h              5 2. 9 9 6 3  
M R TI N F _ o b s                                h              6 1. 8 2 0 8  
M R TI N F _ pr e d                               h              6 1. 8 5 3 6  
A U C 0 _ 2 4                             h* n g/ m L            4 0 8 1. 4 9 4 1  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 2, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 2  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:   Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0        7. 4 1 0                            1. 8 5 3      2. 7 7 9  
      2. 0 0 0        1 0. 8 0                            6. 4 0 5      1 0. 9 6  
      3. 0 0 0        3 7. 8 0                            3 0. 7 1      7 8. 4 6  
      4. 0 0 0        6 8. 1 0                            8 3. 6 6      2 7 1. 4  
      6. 0 0 0        1 9 8. 0                            3 4 9. 8      1 7 3 2.  
      8. 0 6 7        2 2 1. 0                            7 8 2. 7      4 8 0 2.  
      1 2. 0 0        2 0 2. 0                            1 6 1 4. 1. 3 1 2 e + 0 0 4  
      1 6. 0 0        1 9 0. 0                            2 3 9 8. 2. 4 0 7 e + 0 0 4  
      2 4. 0 2        2 0 3. 0                            3 9 7 3. 5. 5 8 0 e + 0 0 4  
      3 6. 0 0 *      1 7 2. 0      1 7 5. 3     -3. 2 6 1      6 2 1 5. 1. 2 2 7 e + 0 0 5      1. 0 0 0  
      4 8. 0 0 *      1 4 6. 0      1 3 7. 0      9. 0 1 4      8 1 1 9. 2. 0 2 3 e + 0 0 5      1. 0 0 0  
      6 0. 0 0 *      1 0 8. 0      1 0 7. 1     0. 9 3 0 3      9 6 3 1. 2. 8 3 6 e + 0 0 5      1. 0 0 0  
      7 2. 0 0 *      8 1. 6 0      8 3. 6 9     -2. 0 8 7 1. 0 7 6 e + 0 0 4 3. 5 7 8 e + 0 0 5      1. 0 0 0  
      9 6. 0 7 *      5 1. 9 0      5 1. 0 6     0. 8 4 4 2 1. 2 3 4 e + 0 0 4 4. 8 9 2 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      2 7. 7 0      3 1. 2 2     -3. 5 2 3 1. 3 2 6 e + 0 0 4 5. 8 7 7 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      1 9. 8 0      1 9. 0 8     0. 7 1 8 9 1. 3 8 3 e + 0 0 4 6. 6 1 9 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      1 2. 1 0      1 1. 6 5     0. 4 5 1 0 1. 4 2 0 e + 0 0 4 7. 2 0 1 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
Pa ge 1 2 7 of 3 3 1
PI
PI


 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 6 6  
R s q _ a dj u st e d                                              0. 9 9 6 1  
C orr _ X Y                                                  -0. 9 9 8 3  
N o _ p oi nt s _l a m b d a _ z                                        8  
L a m b d a _ z                                1/ h               0. 0 2 0 5  
L a m b d a _ z _l o w er                            h              3 6. 0 0 0 0  
L a m b d a _ z _ u p p er                            h              1 6 8. 0 3 3 3  
H L _ L a m b d a _ z                               h              3 3. 7 5 7 5  
Tl a g                                      h               1. 0 0 0 0  
T m a x                                      h               8. 0 6 6 7  
C m a x                                  n g/ m L             2 2 1. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 4 9 1 1  
Tl a st                                     h             1 6 8. 0 3 3 3  
Cl a st                                 n g/ m L              1 2. 1 0 0 0  
A U Cl a st                             h* n g/ m L           1 4 2 0 4. 1 0 0 4  
A U C all                              h* n g/ m L           1 4 2 0 4. 1 0 0 4  
A U CI N F _ o b s                          h* n g/ m L           1 4 7 9 3. 3 9 2 0  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              3 2. 8 7 4 2  
A U C _ % E xtr a p _ o b s                           %               3. 9 8 3 5  
V z _ F _ o b s                                  L            1 4 8 1. 4 5 9 0  
Cl _ F _ o b s                                L/ h              3 0. 4 1 9 0  
A U CI N F _ pr e d                         h* n g/ m L           1 4 7 7 1. 4 2 6 1  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              3 2. 8 2 5 4  
A U C _ % E xtr a p _ pr e d                          %               3. 8 4 0 7  
V z _ F _ pr e d                                 L            1 4 8 3. 6 6 2 0  
Cl _ F _ pr e d                               L/ h              3 0. 4 6 4 2  
A U M Cl a st                          h* h* n g/ m L          7 2 0 1 1 2. 4 5 6 2  
A U M CI N F _ o b s                       h* h* n g/ m L          8 4 7 8 3 2. 6 4 1 4  
A U M C _ % E xtr a p _ o b s                          %              1 5. 0 6 4 3  
A U M CI N F _ pr e d                      h* h* n g/ m L          8 4 3 0 7 1. 8 6 3 4  
A U M C _ % E xtr a p _ pr e d                         %              1 4. 5 8 4 7  
M R Tl a st                                   h              5 0. 6 9 7 5  
M R TI N F _ o b s                                h              5 7. 3 1 1 6  
M R TI N F _ pr e d                               h              5 7. 0 7 4 5  
A U C 0 _ 2 4                             h* n g/ m L            3 9 6 9. 7 0 8 8  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = T E P O, S U B JI D = 
, A P E RI O D = 2, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 3: 2 3  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0        7. 5 9 0                           0. 9 4 8 8     0. 7 1 1 6  
Pa ge 1 2 8 of 3 3 1
PI
PI


      1.000        13.10                            3.535      3.061 
      1.500        37.60                            16.21      20.44 
      2.000        73.30                            43.94      71.19 
      3.000        99.00                            130.1      293.0 
      4.000        126.0                            242.6      693.5 
      6.033        178.0                            551.7      2298. 
      8.000        206.0                            929.3      4974. 
      12.00        238.0                            1817. 1.398e+004 
      16.03        221.0                            2742. 2.693e+004 
      24.00        249.0                            4615. 6.485e+004 
      36.00        254.0                            7633. 1.556e+005 
      48.00        199.0                       1.034e+004 2.685e+005 
      60.00        137.0                       1.233e+004 3.754e+005 
      72.00        118.0                       1.386e+004 4.759e+005 
      96.00        51.10                       1.578e+004 6.339e+005 
      120.0 *      24.10      23.81     0.2927 1.664e+004 7.257e+005      1.000 
      144.0 *      12.90      13.22    -0.3195 1.707e+004 7.820e+005      1.000 
      168.0 *      7.440      7.349    0.09056 1.731e+004 8.189e+005      1.000 
 
 
*) Starred values were included in the estimation of Lambda_z. 
 
 
Final Parameters 
--------------- 
Rsq                                                       0.9987 
Rsq_adjusted                                              0.9974 
Corr_XY                                                  -0.9994 
No_points_lambda_z                                        3 
Lambda_z                                1/h               0.0245 
Lambda_z_lower                            h             119.9833 
Lambda_z_upper                            h             168.0000 
HL_Lambda_z                               h              28.3168 
Tlag                                      h               0.5000 
Tmax                                      h              36.0000 
Cmax                                  ng/mL             254.0000 
Cmax_D                             ng/mL/mg               0.5644 
Tlast                                     h             168.0000 
Clast                                 ng/mL               7.4400 
AUClast                             h*ng/mL           17306.0333 
AUCall                              h*ng/mL           17306.0333 
AUCINF_obs                          h*ng/mL           17609.9759 
AUCINF_D_obs                     h*ng/mL/mg              39.1333 
AUC_%Extrap_obs                           %               1.7260 
Vz_F_obs                                  L            1043.9326 
Cl_F_obs                                L/h              25.5537 
AUCINF_pred                         h*ng/mL           17606.2763 
AUCINF_D_pred                    h*ng/mL/mg              39.1251 
AUC_%Extrap_pred                          %               1.7053 
Vz_F_pred                                 L            1044.1520 
Cl_F_pred                               L/h              25.5591 
AUMClast                          h*h*ng/mL          818857.5400 
AUMCINF_obs                       h*h*ng/mL          882336.7244 
AUMC_%Extrap_obs                          %               7.1944 
AUMCINF_pred                      h*h*ng/mL          881564.0508 
AUMC_%Extrap_pred                         %               7.1131 
MRTlast                                   h              47.3163 
MRTINF_obs                                h              50.1044 
MRTINF_pred                               h              50.0710 
AUC0_24                             h*ng/mL            4614.6449 
 
 
 
Page 129 of 331


Wi n N o nli n C or e O ut p ut 
Wi n N o nli n C or e O ut p ut – – T e p oti ni b M et a b olit e M S C 2 5 7 1 1 0 7 A
T e p oti ni b M et a b olit e M S C 2 5 7 1 1 0 7 A  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 4  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                            0. 0 0 0 0     0. 0 0 0 0  
     0. 2 6 6 7       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 1 7       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0       0. 2 1 4 0                          0. 0 5 1 7 2    0. 0 7 7 5 7  
      2. 0 0 0       0. 4 6 9 0                           0. 2 2 2 5     0. 3 9 2 3  
      3. 0 0 0        1. 2 4 0                            1. 0 7 7      2. 7 2 1  
      4. 0 0 0        2. 3 8 0                            2. 8 8 7      9. 3 4 1  
      6. 0 0 0        2. 8 5 0                            8. 1 1 7      3 5. 9 6  
      8. 0 0 0        4. 1 5 0                            1 5. 1 2      8 6. 2 6  
      1 2. 0 0        4. 7 8 0                            3 2. 9 8      2 6 7. 4  
      1 6. 0 0        6. 4 5 0                            5 5. 4 4      5 8 8. 5  
      2 4. 0 0        7. 6 5 0                            1 1 1. 8      1 7 3 6.  
      3 6. 0 0        5. 9 1 0                            1 9 2. 7      4 1 4 2.  
      4 8. 0 0        6. 3 6 0                            2 6 6. 4      7 2 5 0.  
      6 0. 0 0        4. 1 6 0                            3 2 8. 6 1. 0 5 8 e + 0 0 4  
      7 2. 7 3        3. 8 7 0                            3 7 9. 7 1. 3 9 7 e + 0 0 4  
      9 6. 0 3        3. 1 3 0                            4 6 0. 9 2. 0 7 9 e + 0 0 4  
      1 2 0. 0 *      2. 0 6 0      2. 0 2 5    0. 0 3 4 9 1      5 2 2. 2 2. 7 3 6 e + 0 0 4      1. 0 0 0  
      1 4 4. 0 *      1. 0 5 0      1. 0 8 7   -0. 0 3 6 5 2      5 5 8. 2 3. 2 0 6 e + 0 0 4      1. 0 0 0  
      1 6 8. 0 *     0. 5 9 3 0     0. 5 8 2 9    0. 0 1 0 0 5      5 7 7. 4 3. 5 0 4 e + 0 0 4      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 7 7  
R s q _ a dj u st e d                                              0. 9 9 5 5  
C orr _ X Y                                                  - 0. 9 9 8 9  
N o _ p oi nt s _l a m b d a _ z                                        3  
L a m b d a _ z                                1/ h               0. 0 2 5 9  
L a m b d a _ z _l o w er                            h             1 2 0. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              2 6. 7 1 8 0  
Tl a g                                      h               1. 0 1 6 7  
T m a x                                      h              2 4. 0 0 0 0  
C m a x                                  n g/ m L               7. 6 5 0 0  
Pa ge 1 3 0 of 3 3 1
PI
PI


C m a x _ D                             n g/ m L/ m g               0. 0 1 7 0  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L               0. 5 9 3 0  
A U Cl a st                             h* n g/ m L             5 7 7. 3 7 2 3  
A U C all                              h* n g/ m L             5 7 7. 3 7 2 3  
A U CI N F _ o b s                          h* n g/ m L             6 0 0. 2 3 0 1  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g               1. 3 3 3 8  
A U C _ % E xtr a p _ o b s                           %               3. 8 0 8 2  
V z _ F _ o b s                                  L           2 8 8 9 8. 3 8 5 1  
Cl _ F _ o b s                                L/ h             7 4 9. 7 1 2 5  
A U CI N F _ pr e d                         h* n g/ m L             5 9 9. 8 4 2 7  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g               1. 3 3 3 0  
A U C _ % E xtr a p _ pr e d                          %               3. 7 4 6 0  
V z _ F _ pr e d                                 L           2 8 9 1 7. 0 4 9 4  
Cl _ F _ pr e d                               L/ h             7 5 0. 1 9 6 7  
A U M Cl a st                          h* h* n g/ m L           3 5 0 3 5. 3 7 1 0  
A U M CI N F _ o b s                       h* h* n g/ m L           3 9 7 5 6. 5 4 7 0  
A U M C _ % E xtr a p _ o b s                          %              1 1. 8 7 5 2  
A U M CI N F _ pr e d                      h* h* n g/ m L           3 9 6 7 6. 5 2 8 5  
A U M C _ % E xtr a p _ pr e d                         %              1 1. 6 9 7 5  
M R Tl a st                                   h              6 0. 6 8 0 7  
M R TI N F _ o b s                                h              6 6. 2 3 5 5  
M R TI N F _ pr e d                               h              6 6. 1 4 4 9  
A U C 0 _ 2 4                             h* n g/ m L             1 1 1. 8 3 7 0  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 6  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 1 0 1 0                          0. 0 1 2 6 3    0. 0 1 2 6 3  
      1. 5 0 0       0. 1 9 6 0                          0. 0 8 6 8 8     0. 1 1 1 4  
      2. 0 0 0       0. 3 2 8 0                           0. 2 1 7 9     0. 3 4 8 9  
      3. 0 0 0       0. 7 8 8 0                           0. 7 7 5 9      1. 8 5 9  
      4. 0 0 0        1. 3 5 0                            1. 8 4 5      5. 7 4 1  
      6. 0 0 0        2. 1 3 0                            5. 3 2 5      2 3. 9 2 
      8. 0 0 0        3. 0 3 0                            1 0. 4 8      6 0. 9 4  
      1 2. 0 0        3. 9 6 0                            2 4. 4 6      2 0 4. 5  
      1 6. 0 0        4. 7 9 0                            4 1. 9 6      4 5 2. 8  
      2 4. 0 0        9. 5 6 0                            9 9. 3 6      1 6 7 7.  
      3 6. 0 0        8. 5 1 0                            2 0 7. 7      4 9 1 3.  
      4 8. 0 0        1 1. 2 0                            3 2 5. 9      9 9 7 7.  
      6 0. 0 0        1 0. 1 0                            4 5 3. 6 1. 6 8 6 e + 0 0 4  
      7 2. 0 0        1 2. 2 0                            5 8 7. 4 2. 5 7 7 e + 0 0 4  
Pa ge 1 3 1 of 3 3 1
PI
PI


      9 6. 0 0 *      1 0. 5 0      1 0. 7 8    -0. 2 8 3 5      8 5 9. 3 4. 8 5 2 e + 0 0 4      1. 0 0 0  
      1 2 0. 0 *      7. 7 2 0      7. 3 2 8     0. 3 9 2 1      1 0 7 6. 7. 1 8 2 e + 0 0 4      1. 0 0 0  
      1 4 4. 0 *      4. 8 6 0      4. 9 8 0    -0. 1 1 9 7      1 2 2 5. 9. 1 2 6 e + 0 0 4      1. 0 0 0  
      1 6 8. 0 *      3. 3 8 0      3. 3 8 4  -0. 0 0 3 9 2 0      1 3 2 2. 1. 0 6 4 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 4 6  
R s q _ a dj u st e d                                              0. 9 9 2 0  
C orr _ X Y                                                  -0. 9 9 7 3  
N o _ p oi nt s _l a m b d a _ z                                        4  
L a m b d a _ z                                1/ h               0. 0 1 6 1  
L a m b d a _ z _l o w er                            h              9 6. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              4 3. 0 6 0 7  
Tl a g                                      h               0. 7 5 0 0  
T m a x                                      h              7 2. 0 0 0 0  
C m a x                                  n g/ m L              1 2. 2 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 0 2 7 1  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L               3. 3 8 0 0  
A U Cl a st                             h* n g/ m L            1 3 2 2. 3 6 1 4  
A U C all                              h* n g/ m L            1 3 2 2. 3 6 1 4  
A U CI N F _ o b s                          h* n g/ m L            1 5 3 2. 3 3 8 7  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g               3. 4 0 5 2  
A U C _ % E xtr a p _ o b s                           %              1 3. 7 0 3 1  
V z _ F _ o b s                                  L           1 8 2 4 3. 7 2 0 4  
Cl _ F _ o b s                                L/ h             2 9 3. 6 6 8 8  
A U CI N F _ pr e d                         h* n g/ m L            1 5 3 2. 5 8 2 2  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g               3. 4 0 5 7  
A U C _ % E xtr a p _ pr e d                          %              1 3. 7 1 6 8  
V z _ F _ pr e d                                 L           1 8 2 4 0. 8 2 1 7  
Cl _ F _ pr e d                               L/ h             2 9 3. 6 2 2 1  
A U M Cl a st                          h* h* n g/ m L          1 0 6 4 4 6. 9 7 1 2  
A U M CI N F _ o b s                       h* h* n g/ m L          1 5 4 7 6 7. 6 7 7 1  
A U M C _ % E xtr a p _ o b s                          %              3 1. 2 2 1 4  
A U M CI N F _ pr e d                      h* h* n g/ m L          1 5 4 8 2 3. 7 1 5 5  
A U M C _ % E xtr a p _ pr e d                         %              3 1. 2 4 6 3  
M R Tl a st                                   h              8 0. 4 9 7 6  
M R TI N F _ o b s                                h             1 0 1. 0 0 1 0  
M R TI N F _ pr e d                               h             1 0 1. 0 2 1 5  
A U C 0 _ 2 4                             h* n g/ m L              9 9. 3 6 4 9  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 5  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
Pa ge 1 3 2 of 3 3 1
PI
PI


------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 3 3       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      2. 0 0 0       0. 2 3 4 0                          0. 0 5 8 5 0     0. 1 1 7 0  
      3. 0 0 0       0. 6 3 1 0                           0. 4 9 1 0      1. 2 9 8  
      4. 0 0 0        1. 1 7 0                            1. 3 9 2      4. 5 8 4  
      6. 0 0 0        2. 0 5 0                            4. 6 1 2      2 1. 5 6  
      8. 0 0 0        2. 7 3 0                            9. 3 9 2      5 5. 7 0  
      1 2. 0 0        3. 8 3 0                            2 2. 5 1      1 9 1. 3  
      1 6. 0 0        4. 1 8 0                            3 8. 5 3      4 1 7. 0  
      2 4. 0 0        6. 5 4 0                            8 1. 4 1      1 3 1 2.  
      3 6. 0 0        5. 2 3 0                            1 5 1. 7      3 4 0 6.  
      4 8. 0 0        5. 5 7 0                            2 1 6. 5      6 1 4 0.  
      6 0. 0 0        3. 8 1 0                            2 7 2. 2      9 1 2 2.  
      7 2. 0 0        4. 2 5 0                            3 2 0. 5 1. 2 3 3 e + 0 0 4  
      9 6. 0 0 *      3. 0 4 0      2. 9 4 2    0. 0 9 8 3 6      4 0 7. 2 1. 9 5 5 e + 0 0 4      1. 0 0 0  
      1 2 0. 0 *      1. 6 7 0      1. 7 0 8   -0. 0 3 7 6 0      4 6 2. 1 2. 5 4 1 e + 0 0 4      1. 0 0 0  
      1 4 4. 0 *     0. 9 3 9 0     0. 9 9 1 2   -0. 0 5 2 2 4      4 9 2. 5 2. 9 4 0 e + 0 0 4      1. 0 0 0  
      1 6 8. 0 *     0. 6 0 1 0     0. 5 7 5 4    0. 0 2 5 5 9      5 1 0. 7 3. 2 2 2 e + 0 0 4      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 5 7  
R s q _ a dj u st e d                                              0. 9 9 3 5  
C orr _ X Y                                                  -0. 9 9 7 8  
N o _ p oi nt s _l a m b d a _ z                                        4  
L a m b d a _ z                                1/ h               0. 0 2 2 7  
L a m b d a _ z _l o w er                            h              9 6. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 0. 5 8 6 7  
Tl a g                                      h               1. 5 0 0 0  
T m a x                                      h              2 4. 0 0 0 0  
C m a x                                  n g/ m L               6. 5 4 0 0  
C m a x _ D                             n g/ m L/ m g               0. 0 1 4 5  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L               0. 6 0 1 0  
A U Cl a st                             h* n g/ m L             5 1 0. 7 2 1 4  
A U C all                              h* n g/ m L             5 1 0. 7 2 1 4  
A U CI N F _ o b s                          h* n g/ m L             5 3 7. 2 4 1 9  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g               1. 1 9 3 9  
A U C _ % E xtr a p _ o b s                           %               4. 9 3 6 4  
V z _ F _ o b s                                  L           3 6 9 6 1. 4 8 9 9  
Cl _ F _ o b s                                L/ h             8 3 7. 6 1 1 6  
A U CI N F _ pr e d                         h* n g/ m L             5 3 6. 1 1 2 5  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g               1. 1 9 1 4  
A U C _ % E xtr a p _ pr e d                          %               4. 7 3 6 2  
V z _ F _ pr e d                                 L           3 7 0 3 9. 3 5 0 5  
Cl _ F _ pr e d                               L/ h             8 3 9. 3 7 6 0  
A U M Cl a st                          h* h* n g/ m L           3 2 2 2 1. 9 4 7 9  
A U M CI N F _ o b s                       h* h* n g/ m L           3 7 8 4 7. 6 6 2 7  
A U M C _ % E xtr a p _ o b s                          %              1 4. 8 6 4 1  
A U M CI N F _ pr e d                      h* h* n g/ m L           3 7 6 0 8. 0 9 9 0  
A U M C _ % E xtr a p _ pr e d                         %              1 4. 3 2 1 8  
M R Tl a st                                   h              6 3. 0 9 1 0  
M R TI N F _ o b s                                h              7 0. 4 4 8 1  
M R TI N F _ pr e d                               h              7 0. 1 4 9 6  
A U C 0 _ 2 4                             h* n g/ m L              8 1. 4 1 1 5  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
Pa ge 1 3 3 of 3 3 1
PI


 
                                                 Date:    
 
                                                  
Time:     09:27:26 
 
 
                  WINNONLIN NONCOMPARTMENTAL ANALYSIS PROGRAM
 
                                   7.0.0.2535
 
                            Core Version 04Jun2007 
 
Settings
 
--------  
Model:  Plasma Data, Extravascular 
Administration
 
Number of nonmissing observations:   22
 
Dose time:      0.00
 
Dose amount:      450.00
 
Calculation method:  Linear Trapezoidal Rule for for Increasing Values,
 
                     Log Trapezoidal Rule for Decreasing Values
 
Weighting for lambda_z calculations:  Uniform weighting
 
Lambda_z method:  Find best fit for lambda_z,  Log regression 
 
 
Summary Table 
-------------  
      Time         Conc.      Pred.    Residual      AUC       AUMC      Weight
 
          h       ng/mL       
ng/mL       ng/mL     h*ng/mL   h*h*ng/mL
 
-------------------------------------------------------------------------------
 
     0.0000       0.0000                           0.0000     0.0000 
     0.2500       0.0000                           0.0000     0.0000 
     0.5000       0.0000                           0.0000     0.0000 
     0.7500       0.0000                           0.0000     0.0000 
      1.000       0.0000                           0.0000     0.0000 
      1.500       0.0000                   
        0.0000     0.0000 
      2.000       0.1860                          0.04650    0.09300 
      3.000       0.3490                           0.3140     0.8025 
      4.000       0.7860                           0.8815      2.898 
      6.000        1.480                            3.148      14.92 
      8.000        2.160                            6.788      41.08 
      12.00        3.280                            17.67      154.4 
      16.00        4.430                            33.09      374.8 
      24.00        8.880                            86.33      1511.
 
      36.00        7.980                            187.4      4532.
 
      48.00        8.250                            284.8      8632.
 
      60.00        5.540                            
366.4 1.301e+004 
      72.00        5.970                            435.5 1.758e+004 
      96.00        3.730                            549.8 2.708e+004 
      120.0 *      2.880      2.871   0.008763      628.7 3.555e+004      1.000
 
      144.0 *      1.690      1.700   
-0.01033      682.3 4.257e+004      1.000
 
      168.0 *      1.010      1.007   0.003073      714.0 4.748e+004      1.000
 
 
 
*) Starred values were included in the estimation of Lambda_z.
 
 
 
Final Parameters
 
---------------  
Rsq                                                       0.9999  
Rsq_adjusted                                              0.9998 
Corr_XY                                                  -0.9999
 
No_points_lambda_z                                        3 
Lambda_z                                1/h               0.0218
 
Lambda_z_lower                            h             120.0000
 
Lambda_z_upper                            h             168.0000
 
HL_Lambda_z                               h              31.7520
 
Tlag                                      h               1.5000 
Tmax                                      h              24.0000 
Cmax                                  ng/mL               8.8800
 
Cmax_D                             ng/mL/mg               
0.0197 
Tlast                                     h             168.0000
 
Clast                                 ng/mL               1.0100 
AUClast                             h*ng/mL             713.9567 
AUCall                              h*ng/mL             
713.9567 
AUCINF_obs                          h*ng/mL             760.2233 
AUCINF_D_obs                     h*ng/mL/mg               1.6894 
Page 134 of 331
PI


A U C _ % E xtr a p _ o b s                           %               6. 0 8 5 9  
V z _ F _ o b s                                  L           2 7 1 1 5. 4 9 9 2  
Cl _ F _ o b s                                L/ h             5 9 1. 9 3 1 3  
A U CI N F _ pr e d                         h* n g/ m L             7 6 0. 0 8 2 6  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g               1. 6 8 9 1  
A U C _ % E xtr a p _ pr e d                          %               6. 0 6 8 5  
V z _ F _ pr e d                                 L           2 7 1 2 0. 5 2 1 2  
Cl _ F _ pr e d                               L/ h             5 9 2. 0 4 1 0  
A U M Cl a st                          h* h* n g/ m L           4 7 4 8 3. 5 0 1 7  
A U M CI N F _ o b s                       h* h* n g/ m L           5 7 3 7 5. 6 9 6 6  
A U M C _ % E xtr a p _ o b s                          %              1 7. 2 4 1 1  
A U M CI N F _ pr e d                      h* h* n g/ m L           5 7 3 4 5. 5 9 8 4  
A U M C _ % E xtr a p _ pr e d                         %              1 7. 1 9 7 7  
M R Tl a st                                   h              6 6. 5 0 7 5  
M R TI N F _ o b s                                h              7 5. 4 7 2 2  
M R TI N F _ pr e d                               h              7 5. 4 4 6 5  
A U C 0 _ 2 4                             h* n g/ m L              8 6. 3 2 7 5  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 7  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v a ti o n s:   2 2 
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      2. 0 0 0       0. 2 5 3 0                          0. 0 6 3 2 5     0. 1 2 6 5  
      3. 0 0 0       0. 4 7 6 0                           0. 4 2 7 8      1. 0 9 4  
      4. 0 0 0       0. 9 5 2 0                            1. 1 4 2      3. 7 1 2  
      6. 0 0 0        1. 6 9 0                            3. 7 8 4      1 7. 6 6  
      8. 0 0 0        2. 8 0 0                            8. 2 7 4      5 0. 2 0  
      1 2. 0 0        4. 3 6 0                            2 2. 5 9      1 9 9. 6  
      1 6. 0 0        6. 3 0 0                            4 3. 9 1      5 0 5. 9  
      2 4. 0 0        7. 8 9 0                            1 0 0. 7      1 6 6 7.  
      3 6. 0 0        4. 6 1 0                            1 7 3. 9      3 8 2 5.  
      4 8. 0 0        5. 9 7 0                            2 3 7. 4      6 5 4 0.  
      6 0. 0 0        3. 5 8 0                            2 9 3. 5      9 5 4 0.  
      7 2. 0 0 *      3. 4 3 0      3. 6 2 4    -0. 1 9 3 5      3 3 5. 5 1. 2 3 1 e + 0 0 4      1. 0 0 0  
      9 6. 0 0 *      2. 5 1 0      2. 3 4 6     0. 1 6 3 6      4 0 6. 2 1. 8 2 1 e + 0 0 4      1. 0 0 0  
      1 2 0. 0 *      1. 4 3 0      1. 5 1 9   -0. 0 8 9 3 6      4 5 2. 3 2. 3 1 3 e + 0 0 4      1. 0 0 0  
      1 4 4. 0 *      1. 1 3 0     0. 9 8 3 8     0. 1 4 6 2      4 8 2. 9 2. 7 1 5 e + 0 0 4      1. 0 0 0  
      1 6 8. 0 *     0. 5 8 2 0     0. 6 3 7 1   -0. 0 5 5 0 8      5 0 2. 7 3. 0 2 2 e + 0 0 4      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
Pa ge 1 3 5 of 3 3 1
PI
PI


 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 8 0 0  
R s q _ a dj u st e d                                              0. 9 7 3 3  
C orr _ X Y                                                  -0. 9 8 9 9  
N o _ p oi nt s _l a m b d a _ z                                        5  
L a m b d a _ z                                1/ h               0. 0 1 8 1  
L a m b d a _ z _l o w er                            h              7 2. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 8. 2 8 0 0  
Tl a g                                      h               1. 5 0 0 0  
T m a x                                      h              2 4. 0 0 0 0  
C m a x                                  n g/ m L               7. 8 9 0 0  
C m a x _ D                             n g/ m L/ m g               0. 0 1 7 5  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L               0. 5 8 2 0  
A U Cl a st                             h* n g/ m L             5 0 2. 7 1 4 7  
A U C all                              h* n g/ m L             5 0 2. 7 1 4 7  
A U CI N F _ o b s                          h* n g/ m L             5 3 4. 8 5 6 4  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g               1. 1 8 8 6  
A U C _ % E xtr a p _ o b s                           %               6. 0 0 9 4  
V z _ F _ o b s                                  L           4 6 4 6 4. 5 0 3 2  
Cl _ F _ o b s                                L/ h             8 4 1. 3 4 7 3  
A U CI N F _ pr e d                         h* n g/ m L             5 3 7. 8 9 8 2  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g               1. 1 9 5 3  
A U C _ % E xtr a p _ pr e d                          %               6. 5 4 0 9  
V z _ F _ pr e d                                 L           4 6 2 0 1. 7 4 5 1  
Cl _ F _ pr e d                               L/ h             8 3 6. 5 8 9 5  
A U M Cl a st                          h* h* n g/ m L           3 0 2 2 1. 0 2 2 2  
A U M CI N F _ o b s                       h* h* n g/ m L           3 7 3 9 5. 8 9 7 0  
A U M C _ % E xtr a p _ o b s                          %              1 9. 1 8 6 3  
A U M CI N F _ pr e d                      h* h* n g/ m L           3 8 0 7 4. 9 1 3 6  
A U M C _ % E xtr a p _ pr e d                         %              2 0. 6 2 7 5  
M R Tl a st                                    h              6 0. 1 1 5 7  
M R TI N F _ o b s                                h              6 9. 9 1 7 6  
M R TI N F _ pr e d                               h              7 0. 7 8 4 6  
A U C 0 _ 2 4                             h* n g/ m L             1 0 0. 6 7 3 8  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 5  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S  P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 3 3 3       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
Pa ge 1 3 6 of 3 3 1
PI
PI


     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      2. 0 0 0       0. 2 0 3 0                          0. 0 5 0 7 5     0. 1 0 1 5  
      3. 0 0 0       0. 5 0 5 0                           0. 4 0 4 8      1. 0 6 2  
      4. 0 0 0        1. 1 1 0                            1. 2 1 2      4. 0 4 0  
      6. 0 0 0        1. 6 3 0                            3. 9 5 2      1 8. 2 6 
      8. 0 0 0        2. 7 5 0                            8. 3 3 2      5 0. 0 4  
      1 2. 0 0        4. 1 2 0                            2 2. 0 7      1 9 2. 9  
      1 6. 0 0        5. 4 8 0                            4 1. 2 7      4 6 7. 2  
      2 4. 0 2        8. 2 0 0                            9 6. 1 1      1 6 0 8.  
      3 6. 0 0        6. 7 4 0                            1 8 5. 3      4 2 6 8.  
      4 8. 0 0        7. 4 4 0                            2 7 0. 4      7 8 6 7.  
      6 0. 0 2        4. 5 1 0                            3 4 0. 8 1. 1 6 3 e + 0 0 4  
      7 2. 0 0 *      4. 6 4 0      4. 8 1 9    -0. 1 7 8 7      3 9 5. 6 1. 5 2 5 e + 0 0 4      1. 0 0 0  
      9 6. 0 0 *      3. 0 9 0      3. 0 2 1    0. 0 6 8 9 5      4 8 7. 1 2. 2 8 7 e + 0 0 4      1. 0 0 0  
      1 2 0. 0 *      2. 1 0 0      1. 8 9 4     0. 2 0 6 0      5 4 8. 6 2. 9 4 6 e + 0 0 4      1. 0 0 0  
      1 4 4. 0 *      1. 0 5 0      1. 1 8 7    -0. 1 3 7 5      5 8 5. 0 3. 4 2 1 e + 0 0 4      1. 0 0 0  
      1 6 8. 0 *     0. 7 7 1 0     0. 7 4 4 5    0. 0 2 6 5 3      6 0 6. 6 3. 7 5 8 e + 0 0 4      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 8 6 9  
R s q _ a dj u st e d                                              0. 9 8 2 5  
C orr _ X Y                                                  -0. 9 9 3 4  
N o _ p oi nt s _l a m b d a _ z                                        5  
L a m b d a _ z                                1/ h               0. 0 1 9 5  
L a m b d a _ z _l o w er                            h              7 2. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 5. 6 3 0 2  
Tl a g                                      h               1. 5 0 0 0  
T m a x                                      h              2 4. 0 1 6 7  
C m a x                                  n g/ m L               8. 2 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 0 1 8 2  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L               0. 7 7 1 0  
A U Cl a st                             h* n g/ m L             6 0 6. 6 3 2 9  
A U C all                              h* n g/ m L             6 0 6. 6 3 2 9  
A U CI N F _ o b s                          h* n g/ m L             6 4 6. 2 6 5 0  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g               1. 4 3 6 1  
A U C _ % E xtr a p _ o b s                           %               6. 1 3 2 5  
V z _ F _ o b s                                  L           3 5 7 9 2. 7 0 1 4  
Cl _ F _ o b s                                L/ h             6 9 6. 3 0 8 7  
A U CI N F _ pr e d                         h* n g/ m L             6 4 4. 9 0 1 4  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g               1. 4 3 3 1  
A U C _ % E xtr a p _ pr e d                          %               5. 9 3 4 0  
V z _ F _ pr e d                                 L           3 5 8 6 8. 3 8 3 2  
Cl _ F _ pr e d                               L/ h             6 9 7. 7 8 1 1  
A U M Cl a st                          h* h* n g/ m L           3 7 5 8 0. 0 9 7 0  
A U M CI N F _ o b s                       h* h* n g/ m L           4 6 2 7 5. 5 1 6 6  
A U M C _ % E xtr a p _ o b s                          %              1 8. 7 9 0 5  
A U M CI N F _ pr e d                      h* h* n g/ m L           4 5 9 7 6. 3 3 5 6  
A U M C _ % E xtr a p _ pr e d                         %              1 8. 2 6 2 1  
M R Tl a st                                   h              6 1. 9 4 8 7  
M R TI N F _ o b s                                h              7 1. 6 0 4 5  
M R TI N F _ pr e d                               h              7 1. 2 9 2 0  
A U C 0 _ 2 4                             h* n g/ m L              9 5. 9 6 9 6  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 6  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
Pa ge 1 3 7 of 3 3 1
PI
PI


                            Core Versi
on 04Jun2007 
 
Settings
 
--------  
Model:  Plasma Data, Extravascular Administration
 
Number of nonmissing observations:   22
 
Dose time:      0.00
 
Dose amount:      450.00
 
Calculation method:  Linear Trapezoidal Rule for for Increasing Values,
 
                     Log Trapezoidal Rule for Decreasing Values
 
Weighting for lambda_z calculations:  Uniform weighting
 
Lambda_z method:  
Find best fit for lambda_z,  Log regression 
 
 
Summary Table 
-------------  
      Time         Conc.      Pred.    Residual      AUC       AUMC      Weight
 
          h       ng/mL       ng/mL       ng/mL     h*ng/mL   h*h*ng/mL
 
-------------------------------------------------------------------------------
 
     0.0000       0.0000                           0.0000     0.0000 
     0.2500       0.0000                           0.0000     0.0000 
     0.5000       0.0000                           0.0000     0.0000 
     0.7500       0.1170                          0.01463    0.01097 
      1.000       0.1330                          0.04588    0.03856 
      1.500       0.2620                           0.1446     0.1701 
      2.000       0.4560                           
0.3241     0.4963 
      3.000       0.8440                           0.9741      2.218 
      4.000        1.760                            2.276      7.004 
      6.000        3.380                            7.416      34.32 
      8.000        4.250                            
15.05      88.60 
      12.00        5.750                            35.05      294.6 
      16.00        6.900                            60.35      653.4 
      24.00        11.20                            132.7      2170.
 
      36.00        9.890                            259.1      5946.
 
      48.00        11.50                            387.5 1.139e+004 
      60.00        8.190                            504.5 1.767e+004 
      72.00        9.100                         
   608.2 2.455e+004 
      96.00 *      8.150      8.204   
-0.05434      815.0 4.188e+004      1.000
 
      120.0 *      5.660      5.725   
-0.06549      978.9 5.946e+004      1.000
 
      144.0 *      4.170      3.995     0.1754      1096. 7.485e+004      1.000
 
      168.0 *      2.720      2.788   
-0.06837      1177. 8.748e+004      1.000
 
 
 
*) Starred values were included in the estimation of Lambda_z.
 
 
 
Final Parameters
 
---------------  
Rsq                                                       0.9959  
Rsq_adj
usted                                              0.9939 
Corr_XY                                                  -0.9980
 
No_points_lambda_z                                        4
 
Lambda_z                                1/h               0.0150
 
Lambda_z
_lower                            h              96.0000
 
Lambda_z_upper                            h             168.0000
 
HL_Lambda_z                               h              46.2438
 
Tlag                                      h               0.5000 
Tmax
                                      
h              48.0000 
Cmax                                  ng/mL              11.5000
 
Cmax_D                             ng/mL/mg               0.0256 
Tlast                                     h             168.0000
 
Clast                                 ng/mL               2.7200 
AUClast                             h*ng/mL            1177.4411
 
AUCall                              h*ng/mL            1177.4411
 
AUCINF_obs                          h*ng/mL            1358.9077
 
AUCINF_D_obs                     h*ng/mL/mg               3.0198 
AUC_%Extrap_obs                           %              13.3539 
Vz_F_obs                                  L           22092.7779
 
Cl_F_obs                                L/h             331.1483
 
AUCINF_pred                         h*ng/mL            1363.4689 
AUCINF_D_pred                    h*ng/mL/mg               3.0299 
AUC_%Extrap_pred                          %              13.6437 
Vz_F_pred                                 L           
22018.8711
 
Page 138 of 331


Cl _ F _ pr e d                               L/ h             3 3 0. 0 4 0 5  
A U M Cl a st                           h* h* n g/ m L           8 7 4 7 9. 5 1 6 8  
A U M CI N F _ o b s                       h* h* n g/ m L          1 3 0 0 7 2. 5 6 5 6  
A U M C _ % E xtr a p _ o b s                          %              3 2. 7 4 5 6  
A U M CI N F _ pr e d                      h* h* n g/ m L          1 3 1 1 4 3. 1 5 1 5  
A U M C _ % E xtr a p _ pr e d                         %              3 3. 2 9 4 6  
M R Tl a st                                   h              7 4. 2 9 6 3  
M R TI N F _ o b s                                h              9 5. 7 1 8 5  
M R TI N F _ pr e d                               h              9 6. 1 8 3 5  
A U C 0 _ 2 4                             h* n g/ m L             1 3 2. 7 4 6 1  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 4  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 3 3       0. 1 3 7 0                          0. 0 1 9 4 1    0. 0 2 0 0 6  
      1. 5 0 0       0. 3 3 4 0                           0. 1 2 9 3     0. 1 7 0 0  
      2. 0 1 7       0. 6 1 8 0                           0. 3 7 5 2     0. 6 2 1 4  
      3. 0 0 0        1. 7 6 0                            1. 5 4 4      3. 8 3 0  
      4. 0 0 0        2. 4 3 0                            3. 6 3 9      1 1. 3 3  
      6. 0 0 0        3. 2 3 0                            9. 2 9 9      4 0. 4 3  
      8. 0 0 0        3. 7 0 0                            1 6. 2 3      8 9. 4 1  
      1 2. 0 0        4. 6 4 0                            3 2. 9 1      2 6 0. 0  
      1 6. 0 0        5. 7 2 0                            5 3. 6 3      5 5 4. 4  
      2 4. 0 3        8. 5 7 0                            1 1 1. 0      1 7 4 9.  
      3 6. 0 0        6. 4 3 0                            2 0 0. 2      4 3 9 9.  
      4 8. 0 0        6. 3 6 0                            2 7 6. 9      7 6 2 2.  
      6 0. 0 0        4. 4 9 0                            3 4 1. 4 1. 1 0 8 e + 0 0 4  
      7 2. 0 0 *      4. 3 3 0      4. 4 5 0    -0. 1 2 0 1      3 9 4. 3 1. 4 5 7 e + 0 0 4      1. 0 0 0  
      9 6. 0 0 *      3. 0 6 0      2. 8 4 1     0. 2 1 9 5      4 8 2. 1 2. 1 8 8 e + 0 0 4      1. 0 0 0  
      1 2 0. 3 *      1. 6 8 0      1. 8 0 4    -0. 1 2 4 1      5 3 7. 9 2. 7 8 6 e + 0 0 4      1. 0 0 0  
      1 4 4. 0 *      1. 1 9 0      1. 1 5 7    0. 0 3 2 6 9      5 7 1. 6 3. 2 2 9 e + 0 0 4      1. 0 0 0  
      1 6 8. 0 *      0. 7 3 6 0     0. 7 3 8 7  -0. 0 0 2 7 1 0      5 9 4. 3 3. 5 8 1 e + 0 0 4      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 4 0  
R s q _ a dj u st e d                                              0. 9 9 2 0  
C orr _ X Y                                                  - 0. 9 9 7 0  
Pa ge 1 3 9 of 3 3 1
PI
PI


N o _ p oi nt s _l a m b d a _ z                                        5  
L a m b d a _ z                                1/ h               0. 0 1 8 7  
L a m b d a _ z _l o w er                            h              7 2. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 7. 0 5 4 8  
Tl a g                                      h               0. 7 5 0 0  
T m a x                                      h              2 4. 0 3 3 3  
C m a x                                  n g/ m L               8. 5 7 0 0  
C m a x _ D                             n g/ m L/ m g               0. 0 1 9 0  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L               0. 7 3 6 0  
A U Cl a st                             h* n g/ m L             5 9 4. 3 1 8 8  
A U C all                              h* n g/ m L             5 9 4. 3 1 8 8  
A U CI N F _ o b s                          h* n g/ m L             6 3 3. 6 6 4 5  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g               1. 4 0 8 1  
A U C _ % E xtr a p _ o b s                           %               6. 2 0 9 2  
V z _ F _ o b s                                  L           3 7 9 6 4. 0 3 4 2  
Cl _ F _ o b s                                L/ h             7 1 0. 1 5 5 0  
A U CI N F _ pr e d                         h* n g/ m L             6 3 3. 8 0 9 4  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g               1. 4 0 8 5  
A U C _ % E xtr a p _ pr e d                          %               6. 2 3 0 7  
V z _ F _ pr e d                                 L           3 7 9 5 5. 3 5 5 0  
Cl _ F _ pr e d                               L/ h             7 0 9. 9 9 2 7  
A U M Cl a st                          h* h* n g/ m L           3 5 8 0 5. 1 1 6 7  
A U M CI N F _ o b s                       h* h* n g/ m L           4 4 5 1 8. 5 6 2 7  
A U M C _ % E xtr a p _ o b s                          %              1 9. 5 7 2 6  
A U M CI N F _ pr e d                      h* h* n g/ m L           4 4 5 5 0. 6 5 1 7  
A U M C _ % E xtr a p _ pr e d                         %              1 9. 6 3 0 5  
M R Tl a st                                   h              6 0. 2 4 5 6  
M R TI N F _ o b s                                h              7 0. 2 5 5 7  
M R TI N F _ pr e d                               h              7 0. 2 9 0 3  
A U C 0 _ 2 4                             h* n g/ m L             1 1 0. 7 4 2 1  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 5  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:   Pl a s m a D at a,  E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      2. 0 0 0       0. 1 4 2 0                          0. 0 3 5 5 0    0. 0 7 1 0 0  
      3. 0 0 0       0. 5 7 4 0                           0. 3 9 3 5      1. 0 7 4  
      4. 0 0 0       0. 9 6 2 0                            1. 1 6 2      3. 8 5 9  
      6. 0 0 0        2. 6 2 0                            4. 7 4 4      2 3. 4 3  
Pa ge 1 4 0 of 3 3 1
PI
PI


      8. 0 6 7        3. 9 6 0                            1 1. 5 4      7 2. 6 8  
      1 2. 0 0        4. 6 6 0                            2 8. 5 0      2 4 5. 5  
      1 6. 0 0        5. 5 7 0                            4 8. 9 6      5 3 5. 6  
      2 4. 0 2        8. 0 8 0                            1 0 3. 7      1 6 7 1.  
      3 6. 0 0 *      6. 4 5 0      7. 3 1 5    -0. 8 6 5 5      1 9 0. 4      4 2 5 3.      1. 0 0 0  
      4 8. 0 0 *      7. 0 9 0      5. 9 5 2      1. 1 3 8      2 7 1. 6      7 6 8 8.      1. 0 0 0  
      6 0. 0 0 *      4. 4 5 0      4. 8 4 2    -0. 3 9 2 1      3 3 9. 6 1. 1 3 3 e + 0 0 4      1. 0 0 0  
      7 2. 0 0 *      4. 1 7 0      3. 9 3 9     0. 2 3 0 6      3 9 1. 3 1. 4 7 4 e + 0 0 4      1. 0 0 0  
      9 6. 0 7 *      2. 8 9 0      2. 6 0 4     0. 2 8 5 6      4 7 5. 3 2. 1 7 4 e + 0 0 4      1. 0 0 0  
      1 2 0. 0 *      1. 3 9 0      1. 7 2 5    -0. 3 3 5 3      5 2 4. 4 2. 6 9 7 e + 0 0 4      1. 0 0 0  
      1 4 4. 0 *      1. 2 5 0      1. 1 4 2     0. 1 0 7 7      5 5 6. 0 3. 1 1 4 e + 0 0 4      1. 0 0 0  
      1 6 8. 0 *      0. 7 5 6 0     0. 7 5 5 7  0. 0 0 0 3 3 5 3      5 7 9. 7 3. 4 8 0 e + 0 0 4      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 7 4 4  
R s q _ a dj u st e d                                              0. 9 7 0 1  
C orr _ X Y                                                  -0. 9 8 7 1  
N o _ p oi nt s _l a m b d a _ z                                        8  
L a m b d a _ z                                1/ h               0. 0 1 7 2  
L a m b d a _ z _l o w er                            h              3 6. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 3 3 3  
H L _ L a m b d a _ z                               h              4 0. 3 1 3 9  
Tl a g                                      h               1. 5 0 0 0  
T m a x                                      h              2 4. 0 1 6 7  
C m a x                                  n g/ m L               8. 0 8 0 0  
C m a x _ D                             n g/ m L/ m g               0. 0 1 8 0  
Tl a st                                     h             1 6 8. 0 3 3 3  
Cl a st                                 n g/ m L               0. 7 5 6 0  
A U Cl a st                             h* n g/ m L             5 7 9. 6 5 3 8  
A U C all                              h* n g/ m L             5 7 9. 6 5 3 8  
A U CI N F _ o b s                          h* n g/ m L             6 2 3. 6 2 3 3  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g               1. 3 8 5 8  
A U C _ % E xtr a p _ o b s                           %               7. 0 5 0 6  
V z _ F _ o b s                                  L           4 1 9 6 8. 1 0 2 1  
Cl _ F _ o b s                                L/ h             7 2 1. 5 8 9 5  
A U CI N F _ pr e d                         h* n g/ m L             6 2 3. 6 0 3 8  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g               1. 3 8 5 8  
A U C _ % E xtr a p _ pr e d                          %               7. 0 4 7 7  
V z _ F _ pr e d                                 L           4 1 9 6 9. 4 1 4 5  
Cl _ F _ pr e d                               L/ h             7 2 1. 6 1 2 1  
A U M Cl a st                          h* h* n g/ m L           3 4 7 9 6. 5 4 5 9  
A U M CI N F _ o b s                       h* h* n g/ m L           4 4 7 4 2. 1 6 7 4  
A U M C _ % E xtr a p _ o b s                          %              2 2. 2 2 8 7  
A U M CI N F _ pr e d                      h* h* n g/ m L           4 4 7 3 7. 7 5 6 4  
A U M C _ % E xtr a p _ pr e d                         %              2 2. 2 2 1 1  
M R Tl a st                                   h              6 0. 0 2 9 9  
M R TI N F _ o b s                                h              7 1. 7 4 5 5  
M R TI N F _ pr e d                               h              7 1. 7 4 0 7  
A U C 0 _ 2 4                             h* n g/ m L             1 0 3. 5 3 4 6  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  T i m e:     0 9: 2 7: 2 6 
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
Pa ge 1 4 1 of 3 3 1
PI
PI


Dose amount:      450.00
 
Calculat
ion method:  Linear Trapezoidal Rule for for Increasing Values,
 
                     Log Trapezoidal Rule for Decreasing Values
 
Weighting for lambda_z calculations:  Uniform weighting
 
Lambda_z method:  Find best fit for lambda_z,  Log regression 
 
 
Summary Table 
-------------  
      Time         Conc.      Pred.    Residual      AUC       AUMC      Weight
 
          h       ng/mL       ng/mL       ng/mL     h*ng/mL   h*h*ng/mL
 
-------------------------------------------------------------------------------
 
     0.0000       0.0000                           0.0000     0.0000 
     0.2500       0.0000                           0.0000     0.0000 
     0.5000       0.0000                           
0.0000     0.0000 
     0.7500       0.0000                           0.0000     0.0000 
      1.000       0.1480                          0.01850    0.01850 
      1.500       0.3930                           0.1538     0.2029 
      2. 000       0.7760                           0.4460     0.7383 
      3.000        1.300                            1.484      3.464 
      4.000        1.970                            3.119      9.354 
      6.033        2.590                            7.755      33.25 
      8.000        3.510                            13.75      76.23 
      12.00        4.180                            29.13      232.7 
      16.03        5.340                            48.33      506.5 
      24.00        7.420                            99.16      1557.
 
      36.00        6.960                            185.4      4139.
 
      48.00        6.950                            268.9      7644.
 
      60.00        3.870                            
332.0 1.102e+004 
      72.00        4.220                            380.5 1.423e+004 
      96.00        2.350                            457.2 2.058e+004 
      120.0 *     0.9030     0.9223   
-0.01925      493.5 2.443e+004      1.000
 
      144.0 *     0.5430     0.5205    0.02246      510.5 2.666e+004      1.000
 
      168.0 *     0.2880     0.2942  -
0.006154      520.1 2.815e+004      1.000
 
 
 
*) Starred values were included in the estimation of Lambda_z.
 
 
 
Final Parameters
 
---------------  
Rsq                                                       
0.9959
 
Rsq_adjusted                                              0.9918 
Corr_XY                                                  -0.9980
 
No_points_lambda_z                                        3
 
Lambda_z          
                      1/h               0.0238
 
Lambda_z_lower                            h             119.9833
 
Lambda_z_upper                            h             168.0000
 
HL_Lambda_z                               h              29.1258
 
Tlag                                      h               0.7500 
Tmax                                      h              24.0000 
Cmax                                  ng/mL               7.4200
 
Cmax_D                             ng/mL/mg               0.0165
 
Tlast                                     h             168.0000
 
Clast                                 ng/mL               0.2880 
AUClast                             h*ng/mL             520.1389 
AUCall                              h*ng/mL             520.1389 
AUCINF_obs                          h*ng/mL             532.2405 
AUCINF_D_obs                     h*ng/mL/mg               1.1828 
AUC_%Extrap_obs                           %               2.2737 
Vz_F_obs                                  L           
35526.9137
 
Cl_F_obs                                L/h             845.4824
 
AUCINF_pred                         h*ng/mL             532.4991 
AUCINF_D_pred                    h*ng/mL/mg               1.1833 
AUC_%Extrap_pred                          %      
         2.3212 
Vz_F_pred                                 L           35509.6614
 
Cl_F_pred                               L/h             845.0718
 
AUMClast                          h*h*ng/mL           28153.5601 
AUMCINF_obs                       h*h*ng/mL  
         30695.1496 
AUMC_%Extrap_obs                          %               8.2801 
AUMCINF_pred                      h*h*ng/mL           30749.4583 
AUMC_%Extrap_pred                         %               8.4421 
MRTlast                                   
h              54.1270 
Page 142 of 331


M R TI N F _ o b s                                h              5 7. 6 7 1 6  
M R TI N F _ pr e d                               h              5 7. 7 4 5 6  
A U C 0 _ 2 4                             h* n g/ m L              9 9. 1 5 9 3  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 5  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 3 3 3       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 1 0 3 0                          0. 0 1 3 7 3    0. 0 1 3 7 3  
      1. 5 0 0       0. 2 5 6 0                           0. 1 0 3 5     0. 1 3 5 5  
      2. 0 0 0       0. 5 1 8 0                           0. 2 9 7 0     0. 4 9 0 5  
      3. 0 0 0        1. 3 9 0                            1. 2 5 1      3. 0 9 3  
      4. 0 0 0        2. 1 2 0                            3. 0 0 6      9. 4 1 8  
      6. 0 0 0        2. 5 1 0                            7. 6 3 6      3 2. 9 6 
      8. 0 5 0        3. 2 4 0                            1 3. 5 3      7 5. 1 3  
      1 2. 0 0        3. 8 2 0                            2 7. 4 7      2 1 7. 2  
      1 6. 0 5        4. 5 8 0                            4 4. 4 8      4 5 8. 9  
      2 4. 0 2        6. 2 6 0                            8 7. 6 6      1 3 5 1.  
      3 6. 0 0        4. 6 6 0                            1 5 2. 6      3 2 8 1.  
      4 8. 0 0 *      4. 7 9 0      4. 4 3 4     0. 3 5 6 2      2 0 9. 3      5 6 6 7.      1. 0 0 0  
      6 0. 0 0 *      2. 6 6 0      3. 2 8 2    -0. 6 2 2 1      2 5 2. 8      7 9 8 8.      1. 0 0 0  
      7 2. 0 0 *      3. 0 1 0      2. 4 3 0     0. 5 8 0 5      2 8 6. 8 1. 0 2 5 e + 0 0 4      1. 0 0 0  
      9 5. 7 3 *      1. 3 6 0      1. 3 4 0    0. 0 1 9 7 9      3 3 6. 1 1. 4 3 0 e + 0 0 4      1. 0 0 0  
      1 2 0. 0 *     0. 6 5 9 0     0. 7 2 9 5   -0. 0 7 0 4 8      3 5 9. 6 1. 6 8 0 e + 0 0 4      1. 0 0 0  
      1 4 4. 0 *     0. 3 4 8 0     0. 3 9 9 7   -0. 0 5 1 7 3      3 7 1. 3 1. 8 3 3 e + 0 0 4      1. 0 0 0  
      1 6 8. 0 *     0. 2 5 3 0     0. 2 1 9 0    0. 0 3 3 9 7      3 7 8. 4 1. 9 4 4 e + 0 0 4      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 8 1 0  
R s q _ a dj u st e d                                              0. 9 7 7 2  
C orr _ X Y                                                  -0. 9 9 0 5  
N o _ p oi nt s _l a m b d a _ z                                        7  
L a m b d a _ z                                1/ h               0. 0 2 5 1  
L a m b d a _ z _l o w er                            h              4 8. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              2 7. 6 5 4 1  
Tl a g                                      h               0. 7 3 3 3  
T m a x                                      h              2 4. 0 1 6 7  
Pa ge 1 4 3 of 3 3 1
PI
PI


C m a x                                  n g/ m L               6. 2 6 0 0  
C m a x _ D                             n g/ m L/ m g               0. 0 1 3 9  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L               0. 2 5 3 0  
A U Cl a st                             h* n g/ m L             3 7 8. 4 0 6 6  
A U C all                              h* n g/ m L             3 7 8. 4 0 6 6  
A U CI N F _ o b s                          h* n g/ m L             3 8 8. 5 0 0 4  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g               0. 8 6 3 3  
A U C _ % E xtr a p _ o b s                           %               2. 5 9 8 1  
V z _ F _ o b s                                  L           4 6 2 1 2. 0 3 2 4  
Cl _ F _ o b s                                L/ h            1 1 5 8. 2 9 9 9  
A U CI N F _ pr e d                         h* n g/ m L             3 8 7. 1 4 5 3  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g               0. 8 6 0 3  
A U C _ % E xtr a p _ pr e d                          %               2. 2 5 7 2  
V z _ F _ pr e d                                 L           4 6 3 7 3. 7 9 2 2  
Cl _ F _ pr e d                               L/ h            1 1 6 2. 3 5 4 4  
A U M Cl a st                          h* h* n g/ m L           1 9 4 4 0. 8 7 4 0  
A U M CI N F _ o b s                       h* h* n g/ m L           2 1 5 3 9. 3 3 8 3  
A U M C _ % E xtr a p _ o b s                          %               9. 7 4 2 5  
A U M CI N F _ pr e d                      h* h* n g/ m L           2 1 2 5 7. 6 0 6 1  
A U M C _ % E xtr a p _ pr e d                         %               8. 5 4 6 3  
M R Tl a st                                    h              5 1. 3 7 5 6  
M R TI N F _ o b s                                h              5 5. 4 4 2 3  
M R TI N F _ pr e d                               h              5 4. 9 0 8 6  
A U C 0 _ 2 4                             h* n g/ m L              8 7. 5 5 8 3  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 5  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 1 2 5 0                          0. 0 1 5 6 3    0. 0 1 5 6 3  
      1. 6 0 0       0. 2 2 7 0                           0. 1 2 1 2     0. 1 6 2 1  
      2. 2 1 7       0. 4 8 7 0                           0. 3 4 1 4     0. 6 0 6 9  
      3. 0 0 0        1. 3 7 0                            1. 0 6 9      2. 6 3 9  
      4. 0 0 0        2. 0 5 0                            2. 7 7 9      8. 7 9 4  
      6. 0 0 0        2. 9 7 0                            7. 7 9 9      3 4. 8 1  
      8. 0 0 0        3. 9 8 0                            1 4. 7 5      8 4. 4 7  
      1 2. 0 0        4. 2 0 0                            3 1. 1 1      2 4 9. 0  
      1 6. 0 0        5. 0 9 0                            4 9. 6 9      5 1 2. 6  
      2 4. 0 2        7. 6 4 0                            1 0 0. 7      1 5 7 5.  
      3 6. 0 0        5. 9 5 0                            1 8 1. 7      3 9 8 5.  
      4 8. 0 2        6. 5 3 0                            2 5 6. 7      7 1 5 6.  
      6 0. 0 0        4. 3 2 0                            3 2 0. 8 1. 0 5 9 e + 0 0 4  
Pa ge 1 4 4 of 3 3 1
PI
PI


      7 2. 0 0 *      4. 6 4 0      4. 6 5 4   -0. 0 1 4 1 8      3 7 4. 6 1. 4 1 5 e + 0 0 4      1. 0 0 0  
      9 6. 0 2 *      3. 3 3 0      3. 1 7 6     0. 1 5 4 1      4 6 9. 4 2. 2 0 6 e + 0 0 4      1. 0 0 0  
      1 2 0. 0 *      2. 0 1 0      2. 1 6 8    -0. 1 5 8 2      5 3 2. 1 2. 8 7 7 e + 0 0 4      1. 0 0 0  
      1 4 4. 1 *      1. 5 1 0      1. 4 7 8    0. 0 3 2 4 2      5 7 4. 2 3. 4 3 0 e + 0 0 4      1. 0 0 0  
      1 6 8. 0 *      1. 0 2 0      1. 0 1 0   0. 0 0 9 8 7 8      6 0 4. 1 3. 8 9 4 e + 0 0 4      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 4 2  
R s q _ a dj u st e d                                              0. 9 9 2 2  
C orr _ X Y                                                  -0. 9 9 7 1  
N o _ p oi nt s _l a m b d a _ z                                        5  
L a m b d a _ z                                1/ h               0. 0 1 5 9  
L a m b d a _ z _l o w er                            h              7 2. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              4 3. 5 5 7 2  
Tl a g                                      h               0. 7 5 0 0  
T m a x                                      h              2 4. 0 1 6 7  
C m a x                                  n g/ m L               7. 6 4 0 0  
C m a x _ D                             n g/ m L/ m g               0. 0 1 7 0  
Tl a st                                      h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L               1. 0 2 0 0  
A U Cl a st                             h* n g/ m L             6 0 4. 0 9 2 7  
A U C all                              h* n g/ m L             6 0 4. 0 9 2 7  
A U CI N F _ o b s                          h* n g/ m L             6 6 8. 1 8 9 3  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g               1. 4 8 4 9  
A U C _ % E xtr a p _ o b s                           %               9. 5 9 2 6  
V z _ F _ o b s                                  L           4 2 3 2 0. 1 9 5 4  
Cl _ F _ o b s                                L/ h             6 7 3. 4 6 1 8  
A U CI N F _ pr e d                         h* n g/ m L             6 6 7. 5 6 8 6  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g               1. 4 8 3 5  
A U C _ % E xtr a p _ pr e d                          %               9. 5 0 8 5  
V z _ F _ pr e d                                 L           4 2 3 5 9. 5 4 8 0  
Cl _ F _ pr e d                               L/ h             6 7 4. 0 8 8 1  
A U M Cl a st                          h* h* n g/ m L           3 8 9 3 9. 8 7 5 8  
A U M CI N F _ o b s                       h* h* n g/ m L           5 3 7 3 5. 9 1 5 9  
A U M C _ % E xtr a p _ o b s                          %              2 7. 5 3 4 7  
A U M CI N F _ pr e d                      h* h* n g/ m L           5 3 5 9 2. 6 2 0 6  
A U M C _ % E xtr a p _ pr e d                         %              2 7. 3 4 1 0  
M R Tl a st                                    h              6 4. 4 6 0 1  
M R TI N F _ o b s                                h              8 0. 4 2 0 2  
M R TI N F _ pr e d                               h              8 0. 2 8 0 3  
A U C 0 _ 2 4                             h* n g/ m L             1 0 0. 5 8 7 5  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D =
, A P E RI O D = 2, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3 
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 4  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
Pa ge 1 4 5 of 3 3 1
PI
PI


Summ
ary Table 
-------------  
      T ime         Conc.      Pred.    Residual      AUC       AUMC      Weight
 
          h       ng/mL       ng/mL       ng/mL     h*ng/mL   h*h*ng/mL
 
-------------------------------------------------------------------------------
 
     0.0000       0.0000                           0.0000     0.0000 
     0.2500       0.0000                           0.0000     0.0000 
     0.5167       0.0000                           0.0000     0.0000 
     0.7500       0.0000                           0.0000     0.0000 
      1.000       0.1540                          0.01925    0.01925 
      1.500       0.3570                           0.1470     0.1916 
      2.000        1.090                         
  0.5088     0.8705 
      3.000        1.790                            1.949      4.646 
      4.000        3.230                            4.459      13.79 
      6.000        4.060                            11.75      51.07 
      8.000        6.200                            
22.01      125.0 
      12.00        7.430                            49.27      402.6 
      16.00        7.870                            79.87      832.7 
      24.00        10.30                            152.5      2325.
 
      36. 00        6.690                            252.9      5294.
 
      48.00        7.010                            335.1      8758.
 
      60.00        4.460                            402.8 1.238e+004 
      72.00 *      3.750      3.876    
-0.1260      451.9 1.562e+004      1.000
 
      96.00 *      2.420      2.378    0.04209      524.8 2.167e+004      1.000
 
      120.0 *      1.490      1.459    0.03116      570.8 2.660e+004      1.000
 
      144.0 *     0.9290     0.8950    0.03401      599.3 3.033e+004      1.000
 
      168.0 *     0.5260     0.5491   
-0.02307      616.3 3.297e+004      1.000
 
 
 
*) Starred values were included in the estimation of Lambda_z.
 
 
 
Final Parameters
 
---------------  
Rsq                                                       0.9979  
Rsq_a
djusted                                              0.9972 
Corr_XY                                                  -0.9989
 
No_points_lambda_z                                        5
 
Lambda_z                                1/h               0.0204
 
Lambda_z_lower                            h              72.0000
 
Lambda_z_upper                            h             168.0000
 
HL_Lambda_z                               h              34.0485
 
Tlag                                      h               0.7 500 
Tmax                                      h              24.0000 
Cmax                                  ng/mL              10.3000
 
Cmax_D                             ng/mL/mg               0.0229 
Tlast                                     h             168.0000
 
Clast                                 ng/mL               0.5260 
AUClast                             h*ng/mL             616.3475 
AUCall                              h*ng/mL             616.3475 
AUCINF_obs                          h*ng/mL          
   642.1855 
AUCINF_D_obs                     h*ng/mL/mg               1.4271 
AUC_%Extrap_obs                           %               4.0234 
Vz_F_obs                                  L           34421.0869
 
Cl_F_obs                                L/h             
700.7321
 
AUCINF_pred                         h*ng/mL             643.3188 
AUCINF_D_pred                    h*ng/mL/mg               1.4296 
AUC_%Extrap_pred                          %               4.1925 
Vz_F_pred                                 L           
34360.4492
 
Cl_F_pred                               L/h             699.4977
 
AUMClast                          h*h*ng/mL           32968.3465 
AUMCINF_obs                       h*h*ng/mL           38578.3267 
AUMC_%Extrap_obs                          
%              14.5418 
AUMCINF_pred                      h*h*ng/mL           38824.3903 
AUMC_%Extrap_pred                         %              15.0834 
MRTlast                                   h              53.4899 
MRTINF_obs                                h              60.0735
 
MRTINF_pred                               h              60.3502
 
AUC0_24                             h*ng/mL             152.5488 
 
 
 
WinNonlin 7.0.0.2535 
Page 146 of 331


P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 6  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                            0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0       0. 2 1 2 0                          0. 0 5 3 0 0    0. 0 7 9 5 0  
      2. 0 0 0       0. 3 2 7 0                           0. 1 8 7 8     0. 3 2 2 5  
      3. 0 0 0       0. 6 2 1 0                           0. 6 6 1 8      1. 5 8 1  
      4. 0 0 0       0. 9 7 0 0                            1. 4 5 7      4. 4 5 3  
      6. 0 0 0        1. 5 9 0                            4. 0 1 7      1 7. 8 7  
      8. 0 0 0        1. 9 6 0                            7. 5 6 7      4 3. 0 9  
      1 2. 0 0        2. 9 9 0                            1 7. 4 7      1 4 6. 2  
      1 6. 0 0        3. 5 2 0                            3 0. 4 9      3 3 0. 6  
      2 4. 0 0        5. 8 5 0                            6 7. 9 7      1 1 1 7.  
      3 6. 0 0        6. 5 3 0                            1 4 2. 2      3 3 7 0.  
      4 8. 0 0 *       6. 2 0 0      5. 7 6 3     0. 4 3 7 3      2 1 8. 6      6 5 7 4.      1. 0 0 0  
      6 0. 0 3 *      3. 8 9 0      4. 3 3 3    -0. 4 4 3 5      2 7 8. 2      9 7 6 7.      1. 0 0 0  
      7 2. 0 0 *      3. 4 4 0      3. 2 6 4     0. 1 7 6 2      3 2 2. 0 1. 2 6 5 e + 0 0 4      1. 0 0 0  
      9 6. 0 0 *      1. 6 6 0      1. 8 4 9    -0. 1 8 8 5      3 8 0. 7 1. 7 4 9 e + 0 0 4      1. 0 0 0  
      1 2 0. 0 *      1. 1 9 0      1. 0 4 7     0. 1 4 3 1      4 1 4. 6 2. 1 1 3 e + 0 0 4      1. 0 0 0  
      1 4 4. 0 *     0. 5 7 9 0     0. 5 9 2 9   -0. 0 1 3 9 5      4 3 4. 9 2. 3 7 9 e + 0 0 4      1. 0 0 0  
      1 6 8. 0 *      0. 3 3 1 0     0. 3 3 5 8  -0. 0 0 4 8 2 5      4 4 5. 6 2. 5 4 4 e + 0 0 4      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 2 9  
R s q _ a dj u st e d                                              0. 9 9 1 5  
C orr _ X Y                                                  -0. 9 9 6 4  
N o _ p oi nt s _l a m b d a _ z                                        7  
L a m b d a _ z                                1/ h               0. 0 2 3 7  
L a m b d a _ z _l o w er                            h              4 8. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              2 9. 2 6 1 4  
Tl a g                                      h               1. 0 0 0 0  
T m a x                                      h              3 6. 0 0 0 0  
C m a x                                  n g/ m L               6. 5 3 0 0  
C m a x _ D                             n g/ m L/ m g               0. 0 1 4 5  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a s t                                 n g/ m L               0. 3 3 1 0 
A U Cl a st                             h* n g/ m L             4 4 5. 5 6 0 7  
A U C all                              h* n g/ m L             4 4 5. 5 6 0 7  
A U CI N F _ o b s                          h* n g/ m L             4 5 9. 5 3 3 9  
Pa ge 1 4 7 of 3 3 1
PI
PI


A U CI N F _ D _ o b s                     h* n g/ m L/ m g               1. 0 2 1 2  
A U C _ % E x tr a p _ o b s                           %               3. 0 4 0 7 
V z _ F _ o b s                                  L           4 1 3 3 9. 3 7 0 6  
Cl _ F _ o b s                                L/ h             9 7 9. 2 5 3 0  
A U CI N F _ pr e d                         h* n g/ m L             4 5 9. 7 3 7 6  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g               1. 0 2 1 6  
A U C _ % E xtr a p _ pr e d                          %               3. 0 8 3 7  
V z _ F _ pr e d                                 L           4 1 3 2 1. 0 5 4 2  
Cl _ F _ pr e d                               L/ h             9 7 8. 8 1 9 1  
A U M Cl a st                          h* h* n g/ m L           2 5 4 3 7. 2 6 2 0  
A U M CI N F _ o b s                       h* h* n g/ m L           2 8 3 7 4. 6 4 8 3  
A U M C _ % E xtr a p _ o b s                          %              1 0. 3 5 2 2  
A U M CI N F _ pr e d                      h* h* n g/ m L           2 8 4 1 7. 4 6 8 5  
A U M C _ % E xtr a p _ pr e d                         %              1 0. 4 8 7 2  
M R Tl a st                                   h              5 7. 0 9 0 5  
M R TI N F _ o b s                                h              6 1. 7 4 6 6  
M R TI N F _ pr e d                               h              6 1. 8 1 2 4  
A U C 0 _ 2 4                             h* n g/ m L              6 7. 9 6 7 3  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 5  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0       0. 5 8 0 0                           0. 1 4 5 0     0. 2 1 7 5  
      2. 0 0 0        1. 2 8 0                           0. 6 1 0 0      1. 0 7 5  
      3. 0 0 0        3. 0 2 0                            2. 7 6 0      6. 8 8 5  
      4. 0 0 0        4. 8 6 0                            6. 7 0 0      2 1. 1 4  
      6. 0 0 0        5. 4 6 0                            1 7. 0 2      7 3. 3 4  
      8. 0 0 0        6. 3 4 0                            2 8. 8 2      1 5 6. 8  
      1 2. 0 0        6. 0 2 0                            5 3. 5 3      4 0 3. 5  
      1 6. 0 0        7. 4 4 0                            8 0. 4 5      7 8 6. 1  
      2 4. 0 2        8. 6 8 0                            1 4 5. 1      2 0 9 9.  
      3 6. 0 0        7. 3 0 0                            2 4 0. 6      4 9 4 8.  
      4 8. 0 0        4. 8 7 0                            3 1 2. 6      7 9 4 5.  
      6 0. 0 0        3. 9 1 0                            3 6 5. 1 1. 0 7 7 e + 0 0 4  
      7 2. 0 2        4. 1 1 0                            4 1 3. 3 1. 3 9 5 e + 0 0 4  
      9 6. 0 0        3. 7 3 0                            5 0 7. 2 2. 1 8 3 e + 0 0 4  
      1 2 0. 3 *      3. 9 0 0      3. 7 4 0     0. 1 5 9 9      5 9 9. 9 3. 1 8 7 e + 0 0 4      1. 0 0 0  
      1 4 4. 0 *      2. 1 1 0      2. 2 9 2    -0. 1 8 2 5      6 6 8. 9 4. 0 9 1 e + 0 0 4      1. 0 0 0  
      1 6 8. 1 *      1. 4 5 0      1. 3 9 2    0. 0 5 8 3 4      7 1 1. 4 4. 7 5 0 e + 0 0 4      1. 0 0 0  
 
 
Pa ge 1 4 8 of 3 3 1
PI
PI


*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 7 9 3  
R s q _ a dj u st e d                                              0. 9 5 8 6  
C o rr _ X Y                                                  -0. 9 8 9 6  
N o _ p oi nt s _l a m b d a _ z                                        3  
L a m b d a _ z                                1/ h               0. 0 2 0 7  
L a m b d a _ z _l o w er                            h             1 2 0. 2 8 3 3  
L a m b d a _ z _ u p p er                            h             1 6 8. 1 1 6 7  
H L _ L a m b d a _ z                               h              3 3. 5 3 7 7  
Tl a g                                      h               1. 0 0 0 0  
T m a x                                      h              2 4. 0 1 6 7  
C m a x                                  n g/ m L               8. 6 8 0 0  
C m a x _ D                             n g/ m L/ m g               0. 0 1 9 3  
Tl a st                                     h             1 6 8. 1 1 6 7  
Cl a st                                  n g/ m L               1. 4 5 0 0  
A U Cl a st                             h* n g/ m L             7 1 1. 3 5 6 1  
A U C all                              h* n g/ m L             7 1 1. 3 5 6 1  
A U CI N F _ o b s                          h* n g/ m L             7 8 1. 5 1 3 9  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g               1. 7 3 6 7  
A U C _ % E xtr a p _ o b s                           %               8. 9 7 7 2  
V z _ F _ o b s                                  L           2 7 8 6 0. 1 9 4 0  
Cl _ F _ o b s                                L/ h             5 7 5. 8 0 5 5  
A U CI N F _ pr e d                         h* n g/ m L             7 7 8. 6 9 1 3  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g               1. 7 3 0 4  
A U C _ % E xtr a p _ pr e d                          %               8. 6 4 7 2  
V z _ F _ pr e d                                 L           2 7 9 6 1. 1 8 1 1  
Cl _ F _ pr e d                               L/ h             5 7 7. 8 9 2 6  
A U M Cl a st                          h* h* n g/ m L           4 7 5 0 4. 9 8 2 0  
A U M CI N F _ o b s                       h* h* n g/ m L           6 2 6 9 4. 2 5 7 3  
A U M C _ % E xtr a p _ o b s                          %              2 4. 2 2 7 5  
A U M CI N F _ pr e d                      h* h* n g/ m L           6 2 0 8 3. 1 6 3 4  
A U M C _ % E xtr a p _ pr e d                         %              2 3. 4 8 1 7  
M R Tl a st                                   h              6 6. 7 8 0 9  
M R TI N F _ o b s                                h              8 0. 2 2 1 5  
M R TI N F _ pr e d                               h              7 9. 7 2 7 6  
A U C 0 _ 2 4                             h* n g/ m L             1 4 4. 9 2 4 2  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 6  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
Pa ge 1 4 9 of 3 3 1
PI
PI


     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 8 3 3       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      2. 0 0 0       0. 1 9 6 0                          0. 0 4 9 0 0    0. 0 9 8 0 0  
      3. 0 0 0       0. 7 9 9 0                           0. 5 4 6 5      1. 4 9 3  
      4. 0 0 0        1. 9 3 0                            1. 9 1 1      6 . 5 5 1 
      6. 0 0 0        3. 6 3 0                            7. 4 7 1      3 6. 0 5  
      8. 0 0 0        4. 6 2 0                            1 5. 7 2      9 4. 7 9  
      1 2. 0 0        5. 7 9 0                            3 6. 5 4      3 0 7. 7  
      1 6. 0 0        6. 0 0 0                            6 0. 1 2      6 3 8. 6  
      2 4. 0 0        8. 5 0 0                            1 1 8. 1      1 8 3 9.  
      3 6. 0 0        5. 9 3 0                            2 0 3. 8      4 3 7 8.  
      4 8. 0 0        6. 7 5 0                            2 7 9. 9      7 6 0 2.  
      6 0. 0 0        5. 7 5 0                             3 5 4. 7 1. 1 6 3 e + 0 0 4  
      7 2. 0 0 *      6. 7 0 0      6. 9 0 9    -0. 2 0 8 8      4 2 9. 4 1. 6 6 0 e + 0 0 4      1. 0 0 0  
      9 6. 0 0 *      4. 9 2 0      4. 7 5 3     0. 1 6 7 3      5 6 7. 7 2. 8 1 3 e + 0 0 4      1. 0 0 0  
      1 2 0. 0 *      3. 0 7 0      3. 2 7 0    -0. 1 9 9 6      6 6 1. 9 3. 8 2 1 e + 0 0 4      1. 0 0 0  
      1 4 4. 0 *      2. 6 0 0      2. 2 4 9     0. 3 5 0 8      7 2 9. 8 4. 7 1 5 e + 0 0 4      1. 0 0 0  
      1 6 8. 0 *      1. 4 2 0      1. 5 4 7    -0. 1 2 7 3      7 7 6. 6 5. 4 4 0 e + 0 0 4      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 7 6 0  
R s q _ a dj u st e d                                              0. 9 6 7 9  
C orr _ X Y                                                  -0. 9 8 7 9  
N o _ p oi nt s _l a m b d a _ z                                        5 
L a m b d a _ z                                1/ h               0. 0 1 5 6  
L a m b d a _ z _l o w er                            h              7 2. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              4 4. 4 7 1 7  
Tl a g                                      h               1. 5 0 0 0  
T m a x                                      h              2 4. 0 0 0 0  
C m a x                                  n g/ m L               8. 5 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 0 1 8 9  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L               1. 4 2 0 0  
A U Cl a st                             h* n g/ m L             7 7 6. 5 8 6 3  
A U C all                              h* n g/ m L             7 7 6. 5 8 6 3  
A U CI N F _ o b s                          h* n g/ m L             8 6 7. 6 9 2 3  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g               1. 9 2 8 2  
A U C _ % E xtr a p _ o b s                           %              1 0. 4 9 9 8  
V z _ F _ o b s                                  L           3 3 2 7 4. 0 2 5 0  
Cl _ F _ o b s                                L/ h             5 1 8. 6 1 7 0  
A U CI N F _ pr e d                         h* n g/ m L             8 7 5. 8 5 9 8  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g               1. 9 4 6 4  
A U C _ % E xtr a p _ p r e d                          %              1 1. 3 3 4 4 
V z _ F _ pr e d                                 L           3 2 9 6 3. 7 3 7 6  
Cl _ F _ pr e d                               L/ h             5 1 3. 7 8 0 8  
A U M Cl a st                          h* h* n g/ m L           5 4 3 9 6. 3 7 2 9  
A U M CI N F _ o b s                       h* h* n g/ m L           7 5 5 4 7. 4 5 9 5  
A U M C _ % E xtr a p _ o b s                          %              2 7. 9 9 7 1  
A U M CI N F _ pr e d                      h* h* n g/ m L           7 7 4 4 3. 6 3 8 1  
A U M C _ % E xtr a p _ pr e d                         %              2 9. 7 6 0 0  
M R Tl a st                                   h              7 0. 0 4 5 5  
M R TI N F _ o b s                                h              8 7. 0 6 7 1  
M R TI N F _ pr e d                               h              8 8. 4 2 0 1  
A U C 0 _ 2 4                             h* n g/ m L             1 1 8. 1 2 1 0  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 7  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
Pa ge 1 5 0 of 3 3 1
PI
PI


                                   7.0.0.2535
 
                            Core Version 04Jun2007 
 
Settings
 
--------  
Model:  Plasma Data, Extravascular Administration
 
Number of nonmissing observations:   22
 
Dose time:      0.00
 
Dose amount:      450.00
 
Calculation method:  Linear Trapezoidal Rule for for Increasing Values,
 
                     Log Trapezoidal Rule for Decreasing Values
 
Weighting for lambda_z calculations:  Uniform weighting
 
Lambda_z method:  
Find best fit for lambda_z,  Log regression 
 
 
Summary Table 
-------------  
      Time         Conc.      Pred.    Residual      AUC       AUMC      Weight
 
          h       ng/mL       ng/mL       ng/mL     h*ng/mL   h*h*ng/mL
 
-------------------------------------------------------------------------------
 
     0.0000       0.0000                           0.0000     0.0000 
     0.2500       0.0000                           0.0000     0.0000 
     0.5000       0.0000                           0.0000     0.0000 
     0.7500       0.0000                           0.0000     0.0000 
      1.000       0.1240                          0.01550    0.01550 
      1.500       0.2380                           0.1060     0.1358 
      2.000       0.4130                           
0.2688     0.4315 
      3.000       0.9250                           0.9378      2.232 
      4.000        1.380                            2.090      6.380 
      6.000        3.010                            6.480      29.96 
      8.000        4.020                            
13.51      80.18 
      12.00        5.740                            33.03      282.3 
      16.00        7.140                            58.79      648.5 
      24.02        10.20                            128.3      2088.
 
      36.00        7.230                            231.7      5156.
 
      48.00        8.860                            328.3      9270.
 
      60.00        7.620                            426.9 1.458e+004 
      72.00        8.200                            521.9 2.087e+004 
      96.00        6.360                            695.6 3.538e+004 
      120.0 *      3.610      3.620   
-0.01034      812.2 4.783e+004      1.000
 
      144.0 *      2.900      2.883    
0.01654      890.0 5.807e+004      1.000
 
      168.0 *      2.290      2.297  
-0.006559      952.0 6.771e+004      1.000
 
 
 
*) Starred values were included in the estimation of Lambda_z.
 
 
 
Final Parameters
 
---------------  
Rsq                                                       0.9995
 
Rsq_adjusted                                              0.9991 
Corr_XY                                                  -0.9998
 
No_points_lambda_z                                        3
 
Lambda_z                                
1/h               0.0095
 
Lambda_z_lower                            h             120.0000
 
Lambda_z_upper                            h             168.0000
 
HL_Lambda_z                               h              73.0982
 
Tlag                                      h               0.7500 
Tmax                                      h              24.0167 
Cmax                                  ng/mL              10.2000
 
Cmax_D                             ng/mL/mg               0.0227
 
Tlast                                     h             168.0000
 
Clast                                 ng/mL               2.2900 
AUClast                             h*ng/mL             951.9930 
AUCall                              h*ng/mL             951.9930 
AUCINF_obs                          h*ng/mL            1193.4926 
AUCINF_D_obs                     h*ng/mL/mg               2.6522 
AUC_%Extrap_obs                           %              20.2347
 
Vz_F_obs                                  L           39762.5085
 
Cl_F_obs                                L/h             377.0446
 
AUCINF_pred                         h*ng/mL            1194.1844 
AUCINF_D_pred                    h*ng/mL/mg               
2.6537 
AUC_%Extrap_pred                          %              20.2809 
Page 151 of 331


V z _ F _ pr e d                                 L           3 9 7 3 9. 4 7 5 3  
Cl _ F _ pr e d                               L/ h             3 7 6. 8 2 6 2  
A U M Cl a st                          h* h* n g/ m L           6 7 7 1 3. 0 1 3 9  
A U M CI N F _ o b s                       h* h* n g/ m L          1 3 3 7 5 3. 1 0 9 6  
A U M C _ % E xtr a p _ o b s                          %              4 9. 3 7 4 6  
A U M CI N F _ pr e d                      h* h* n g/ m L          1 3 3 9 4 2. 2 7 5 4  
A U M C _ % E xtr a p _ pr e d                         %              4 9. 4 4 6 1  
M R Tl a st                                   h              7 1. 1 2 7 6  
M R TI N F _ o b s                                h             1 1 2. 0 6 8 7  
M R TI N F _ pr e d                               h             1 1 2. 1 6 2 1  
A U C 0 _ 2 4                             h* n g/ m L             1 2 8. 1 2 4 8  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 6  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v a ti o n s:   2 2 
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0       0. 2 0 6 0                          0. 0 5 1 5 0    0. 0 7 7 2 5  
      2. 0 0 0       0. 4 9 3 0                           0. 2 2 6 3     0. 4 0 1 0  
      3. 0 0 0        1. 0 3 0                           0. 9 8 7 8      2. 4 3 9  
      4. 0 0 0        1. 8 1 0                            2. 4 0 8      7. 6 0 4  
      6. 0 0 0        2. 6 8 0                            6. 8 9 8      3 0. 9 2  
      8. 0 0 0        3. 6 5 0                            1 3. 2 3      7 6. 2 0  
      1 2. 0 0        5. 8 4 0                            3 2. 2 1      2 7 4. 8  
      1 6. 0 0        7. 1 3 0                            5 8. 1 5      6 4 3. 1  
      2 4. 0 0        1 0. 2 0                            1 2 7. 5      2 0 7 9.  
      3 6. 0 3        9. 0 3 0                            2 4 3. 0      5 5 3 3.  
      4 8. 0 0        8. 7 6 0                            3 4 9. 5 1. 0 0 0 e + 0 0 4  
      6 0. 0 0        5. 5 6 0                            4 3 3. 9 1. 4 5 3 e + 0 0 4  
      7 2. 0 0        4. 8 2 0                            4 9 6. 1 1. 8 6 2 e + 0 0 4  
      9 6. 0 0        3. 1 3 0                            5 9 0. 1 2. 6 4 3 e + 0 0 4  
      1 2 0. 0 *      1. 3 9 0      1. 3 9 9  -0. 0 0 8 7 2 9      6 4 1. 5 3. 1 9 0 e + 0 0 4      1. 0 0 0  
      1 4 4. 0 *     0. 9 0 3 0     0. 8 9 1 8    0. 0 1 1 2 4      6 6 8. 6 3. 5 4 6 e + 0 0 4      1. 0 0 0  
      1 6 8. 0 *      0. 5 6 5 0     0. 5 6 8 5  -0. 0 0 3 5 4 8      6 8 5. 9 3. 8 1 4 e + 0 0 4      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 9 4  
R s q _ a dj u st e d                                              0. 9 9 8 8  
Pa ge 1 5 2 of 3 3 1
PI
PI


C orr _ X Y                                                  -0. 9 9 9 7  
N o _ p oi nt s _ l a m b d a _ z                                        3 
L a m b d a _ z                                1/ h               0. 0 1 8 8  
L a m b d a _ z _l o w er                            h             1 2 0. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 6. 9 5 8 3  
Tl a g                                      h               1. 0 0 0 0  
T m a x                                      h              2 4. 0 0 0 0  
C m a x                                  n g/ m L              1 0. 2 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 0 2 2 7  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L               0. 5 6 5 0  
A U Cl a st                             h* n g/ m L             6 8 5. 8 9 3 6  
A U C all                              h* n g/ m L             6 8 5. 8 9 3 6  
A U CI N F _ o b s                          h* n g/ m L             7 1 6. 0 1 9 1  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g               1. 5 9 1 2  
A U C _ % E xtr a p _ o b s                           %               4. 2 0 7 4  
V z _ F _ o b s                                  L           3 3 5 0 9. 9 7 1 5  
Cl _ F _ o b s                                L/ h             6 2 8. 4 7 4 8  
A U CI N F _ pr e d                         h* n g/ m L             7 1 6. 2 0 8 3  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g               1. 5 9 1 6  
A U C _ % E xtr a p _ pr e d                          %               4. 2 3 2 7  
V z _ F _ pr e d                                 L           3 3 5 0 1. 1 2 0 2  
Cl _ F _ pr e d                               L/ h             6 2 8. 3 0 8 8  
A U M Cl a st                          h* h* n g/ m L           3 8 1 3 9. 9 7 3 2  
A U M CI N F _ o b s                       h* h* n g/ m L           4 4 8 0 7. 3 3 9 5  
A U M C _ % E xtr a p _ o b s                          %              1 4. 8 8 0 1  
A U M CI N F _ pr e d                      h* h* n g/ m L           4 4 8 4 9. 2 0 8 5  
A U M C _ % E xtr a p _ pr e d                         %              1 4. 9 5 9 5  
M R Tl a st                                   h              5 5. 6 0 6 3  
M R TI N F _ o b s                                h              6 2. 5 7 8 4  
M R TI N F _ pr e d                               h              6 2. 6 2 0 3  
A U C 0 _ 2 4                             h* n g/ m L             1 2 7. 4 6 7 8  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 5  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:       0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n 
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 1 4 0 0                          0. 0 1 7 5 0    0. 0 1 3 1 3  
      1. 0 0 0       0. 2 3 6 0                          0. 0 6 4 5 0    0. 0 5 5 7 5  
      1. 5 0 0       0. 6 4 3 0                           0. 2 8 4 3     0. 3 5 5 9  
      2. 0 0 0        1. 0 3 0                           0. 7 0 2 5      1. 1 1 2  
      3. 0 0 0        1. 8 3 0                            2. 1 3 3      4. 8 8 7  
      4. 0 0 0        2. 7 3 0                            4. 4 1 3      1 3. 0 9  
Pa ge 1 5 3 of 3 3 1
PI
PI


      6. 0 0 0        3. 2 9 0                            1 0. 4 3      4 3. 7 5 
      8. 0 0 0        4. 0 7 0                            1 7. 7 9      9 6. 0 5  
      1 2. 0 0        5. 0 1 0                            3 5. 9 5      2 8 1. 4  
      1 6. 0 0        6. 2 3 0                            5 8. 4 3      6 0 1. 0  
      2 4. 0 0        8. 7 0 0                            1 1 8. 2      1 8 3 5.  
      3 6. 0 0        7. 8 7 0                            2 1 7. 5      4 8 0 5.  
      4 8. 0 0        9. 1 3 0                            3 1 9. 5      9 1 3 4.  
      6 0. 0 0        7. 9 0 0                            4 2 1. 5 1. 4 6 3 e + 0 0 4  
      7 2. 0 2        7. 7 2 0                            5 1 5. 3 2. 0 8 2 e + 0 0 4  
      9 6. 0 0        5. 0 1 0                            6 6 5. 7 3. 3 3 2 e + 0 0 4  
      1 2 0. 0 *      5. 2 7 0      5. 0 6 8     0. 2 0 2 2      7 8 9. 0 4. 6 6 8 e + 0 0 4      1. 0 0 0  
      1 4 4. 1 *      2. 6 8 0      2. 8 9 9    -0. 2 1 8 8      8 8 1. 2 5. 8 7 3 e + 0 0 4      1. 0 0 0  
      1 6 8. 0 *      1. 7 3 0      1. 6 6 3    0. 0 6 6 7 5      9 3 3. 1 6. 6 7 9 e + 0 0 4      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 8 5 3  
R s q _ a dj u st e d                                              0. 9 7 0 7  
C orr _ X Y                                                  -0. 9 9 2 6  
N o _ p oi nt s _l a m b d a _ z                                        3  
L a m b d a _ z                                1/ h               0. 0 2 3 2  
L a m b d a _ z _l o w er                            h             1 2 0. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              2 9. 8 6 2 9  
Tl a g                                      h               0. 5 0 0 0  
T m a x                                      h              4 8. 0 0 0 0  
C m a x                                  n g/ m L               9. 1 3 0 0  
C m a x _ D                             n g/ m L/ m g               0. 0 2 0 3  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L               1. 7 3 0 0  
A U Cl a st                             h* n g/ m L             9 3 3. 1 4 2 0  
A U C all                              h* n g/ m L             9 3 3. 1 4 2 0  
A U CI N F _ o b s                          h* n g/ m L            1 0 0 7. 6 7 5 7  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g               2. 2 3 9 3  
A U C _ % E xtr a p _ o b s                           %               7. 3 9 6 6  
V z _ F _ o b s                                  L           1 9 2 3 9. 7 0 0 0  
Cl _ F _ o b s                                L/ h             4 4 6. 5 7 2 3  
A U CI N F _ pr e d                         h* n g/ m L            1 0 0 4. 8 0 0 0  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g               2. 2 3 2 9  
A U C _ % E xtr a p _ pr e d                          %               7. 1 3 1 6  
V z _ F _ pr e d                                 L           1 9 2 9 4. 7 6 2 8  
Cl _ F _ pr e d                               L/ h             4 4 7. 8 5 0 3  
A U M Cl a st                          h* h* n g/ m L           6 6 7 8 5. 9 2 8 7  
A U M CI N F _ o b s                       h* h* n g/ m L           8 2 5 1 8. 7 2 9 8  
A U M C _ % E xtr a p _ o b s                          %              1 9. 0 6 5 7  
A U M CI N F _ pr e d                      h* h* n g/ m L           8 1 9 1 1. 7 2 3 5  
A U M C _ % E xtr a p _ pr e d                         %              1 8. 4 6 6 0  
M R Tl a st                                    h              7 1. 5 7 1 0  
M R TI N F _ o b s                                h              8 1. 8 9 0 2  
M R TI N F _ pr e d                               h              8 1. 5 2 0 4  
A U C 0 _ 2 4                             h* n g/ m L             1 1 8. 1 5 2 5  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 7  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M 
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
Pa ge 1 5 4 of 3 3 1
PI
PI


Dose time:      0.00
 
Dose amount:
      450.00
 
Calculation method:  Linear Trapezoidal Rule for for Increasing Values,
 
                     Log Trapezoidal Rule for Decreasing Values
 
Weighting for lambda_z calculations:  Uniform weighting
 
Lambda_z method:  Find best fit for lambda_z,  Log regression 
 
 
Summary Table 
-------------  
      Time         Conc.      Pred.    Residual      AUC       AUMC      Weight
 
          h       ng/mL       ng/mL       ng/mL     h*ng/mL   h*h*ng/mL
 
-------------------------------------------------------------------------------
 
     0.0000       0.0000                           0.0000     0.0000 
     0.2500       0.0000                           0.0000     0.0000 
     0.5000       0.0000                           0.0000     0.0000 
     0.7500       0.0000                     
      0.0000     0.0000 
      1.050       0.0000                           0.0000     0.0000 
      1.500       0.1210                          0.02723    0.04084 
      2.000       0.4080                           0.1595     0.2902 
      3.000       0.6600 
                          0.6935      1.688 
      4.000        1.260                            1.653      5.198 
      6.000        1.750                            4.663      20.74 
      8.017        2.530                            8.979      51.78 
      12.00        4.020                            22.02      188.3 
      16.03        4.940                            40.09      445.3 
      24.00        9.080                            95.94      1629.
 
      36.07        6.290                         
   187.6      4349.
 
      48.00        6.990                            266.9      7705.
 
      60.00        4.500                            334.7 1.134e+004 
      72.00 *      5.540      5.636   
-0.09628      395.0 1.535e+004      1.000
 
      96.00 *      
3.410      3.411  
-0.001146      500.3 2.410e+004      1.000
 
      120.0 *      2.080      2.064    0.01553      564.9 3.101e+004      1.000
 
      144.0 *      1.320      1.249    0.07056      605.0 3.627e+004      1.000
 
      168.0 *     0.7230     0.7562   
-0.03318      628.8 3.995e+004      1.000
 
 
 
*) Starred values were included in the estimation of Lambda_z.
 
 
 
Final Parameters
 
---------------  
Rsq                                                       0.9979  
Rsq_adjusted                                 
             0.9972 
Corr_XY                                                  -0.9989
 
No_points_lambda_z                                        5
 
Lambda_z                                1/h               0.0209
 
Lambda_z_lower                            h              
72.0000
 
Lambda_z_upper                            h             168.0000
 
HL_Lambda_z                               h              33.1269
 
Tlag                                      h               1.0500 
Tmax                                      h              24.0000 
Cmax                                  ng/mL               9.0800
 
Cmax_D                             ng/mL/mg               0.0202 
Tlast                                     h             168.0000
 
Clast                                 ng/mL               0.7230 
AUClast                             h*ng/mL             628.7930 
AUCall                              h*ng/mL             628.7930 
AUCINF_obs                          h*ng/mL             6
63.3466 
AUCINF_D_obs                     h*ng/mL/mg               1.4741 
AUC_%Extrap_obs                           %               5.2090 
Vz_F_obs                                  L           32421.0533
 
Cl_F_obs                                L/h          
   678.3783
 
AUCINF_pred                         h*ng/mL             664.9322 
AUCINF_D_pred                    h*ng/mL/mg               1.4776 
AUC_%Extrap_pred                          %               5.4350 
Vz_F_pred                                 L      
     32343.7429
 
Cl_F_pred                               L/h             676.7607
 
AUMClast                          h*h*ng/mL           39951.6688 
AUMCINF_obs                       h*h*ng/mL           47408.0614 
AUMC_%Extrap_obs                          %  
            15.7281 
AUMCINF_pred                      h*h*ng/mL           47750.2165 
AUMC_%Extrap_pred                         %              16.3320 
Page 155 of 331


M R Tl a st                                   h              6 3. 5 3 7 1  
M R TI N F _ o b s                                h              7 1. 4 6 8 0  
M R TI N F _ pr e d                               h              7 1. 8 1 2 2  
A U C 0 _ 2 4                             h* n g/ m L              9 5. 9 4 0 2  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 7  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      2. 0 0 0       0. 1 1 3 0                          0. 0 2 8 2 5    0. 0 5 6 5 0  
      3. 0 0 0       0. 2 9 8 0                           0. 2 3 3 8     0. 6 1 6 5  
      4. 0 0 0       0. 6 8 4 0                           0. 7 2 4 8      2. 4 3 2  
      6. 0 0 0        1. 9 1 0                            3. 3 1 9      1 6. 6 3  
      8. 0 0 0        2. 7 3 0                            7. 9 5 9      4 9. 9 3  
      1 2. 0 3        4. 3 3 0                            2 2. 2 0      1 9 9. 0  
      1 6. 0 0        5. 3 1 0                            4 1. 3 2      4 7 0. 9  
      2 4. 0 0        7. 8 4 0                            9 3. 9 2      1 5 6 3.  
      3 6. 0 0        5. 4 8 0                            1 7 3. 0      3 9 0 7.  
      4 8. 0 0 *      5. 9 6 0      5. 8 1 4     0. 1 4 5 6      2 4 1. 6      6 8 0 8.      1. 0 0 0  
      6 0. 0 0 *      3. 9 1 0      4. 4 3 6    -0. 5 2 6 5      3 0 0. 0      9 9 3 4.      1. 0 0 0  
      7 2. 0 0 *      3. 7 5 0      3. 3 8 5     0. 3 6 4 9      3 4 5. 9 1. 2 9 7 e + 0 0 4      1. 0 0 0  
      9 6. 0 7 *      2. 0 6 0      1. 9 6 8    0. 0 9 2 1 4      4 1 3. 8 1. 8 5 9 e + 0 0 4      1. 0 0 0  
      1 2 0. 1 *      1. 1 6 0      1. 1 4 6    0. 0 1 3 8 9      4 5 1. 4 2. 2 6 1 e + 0 0 4      1. 0 0 0  
      1 4 4. 0 *     0. 5 8 9 0     0. 6 6 8 0   -0. 0 7 9 0 2      4 7 1. 6 2. 5 2 5 e + 0 0 4      1. 0 0 0  
      1 6 8. 0 *     0. 4 1 6 0     0. 3 8 8 9    0. 0 2 7 0 8      4 8 3. 5 2. 7 1 0 e + 0 0 4      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 2 0  
R s q _ a dj u st e d                                              0. 9 9 0 3  
C orr _ X Y                                                  -0. 9 9 6 0  
N o _ p oi nt s _l a m b d a _ z                                        7  
L a m b d a _ z                                1/ h               0. 0 2 2 5  
L a m b d a _ z _l o w er                            h              4 8. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 0. 7 5 2 8  
Tl a g                                      h               1. 5 0 0 0  
Pa ge 1 5 6 of 3 3 1
PI
PI


T m a x                                      h              2 4. 0 0 0 0  
C m a x                                  n g/ m L               7. 8 4 0 0  
C m a x _ D                             n g/ m L/ m g               0. 0 1 7 4  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L               0. 4 1 6 0  
A U Cl a st                             h* n g/ m L             4 8 3. 5 4 2 8  
A U C all                              h* n g/ m L             4 8 3. 5 4 2 8  
A U CI N F _ o b s                           h* n g/ m L             5 0 1. 9 9 9 5  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g               1. 1 1 5 6  
A U C _ % E xtr a p _ o b s                           %               3. 6 7 6 6  
V z _ F _ o b s                                  L           3 9 7 7 1. 2 0 7 9  
Cl _ F _ o b s                                L/ h             8 9 6. 4 1 5 2  
A U CI N F _ pr e d                         h* n g/ m L             5 0 0. 7 9 8 0  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g               1. 1 1 2 9  
A U C _ % E xtr a p _ pr e d                          %               3. 4 4 5 5  
V z _ F _ pr e d                                 L           3 9 8 6 6. 6 2 2 8  
Cl _ F _ pr e d                               L/ h             8 9 8. 5 6 5 8  
A U M Cl a st                          h* h* n g/ m L           2 7 0 9 9. 5 5 2 2  
A U M CI N F _ o b s                       h* h* n g/ m L           3 1 0 1 9. 1 3 4 6  
A U M C _ % E xtr a p _ o b s                          %              1 2. 6 3 6 0  
A U M CI N F _ pr e d                      h* h* n g/ m L           3 0 7 6 3. 9 8 4 1  
A U M C _ % E xtr a p _ pr e d                         %              1 1. 9 1 1 4  
M R Tl a st                                   h              5 6. 0 4 3 7  
M R TI N F _ o b s                                h              6 1. 7 9 1 2  
M R TI N F _ pr e d                               h              6 1. 4 2 9 9  
A U C 0 _ 2 4                             h* n g/ m L              9 3. 9 1 5 8  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 6  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0       0. 2 6 3 0                          0. 0 6 5 7 5    0. 0 9 8 6 3  
      2. 0 0 0       0. 3 6 7 0                           0. 2 2 3 3     0. 3 8 0 8  
      3. 0 0 0        1. 0 1 0                           0. 9 1 1 8      2. 2 6 3  
      4. 0 0 0        1. 9 5 0                            2. 3 9 2      7. 6 7 8  
      6. 0 0 0        3. 1 2 0                            7. 4 6 2      3 4. 2 0  
      8. 0 0 0        4. 3 6 0                            1 4. 9 4      8 7. 8 0  
      1 2. 0 0        5. 8 4 0                            3 5. 3 4      2 9 7. 7  
      1 6. 0 0        7. 5 0 0                            6 2. 0 2      6 7 7. 9  
      2 4. 0 2        1 1. 3 0                            1 3 7. 4      2 2 4 7.  
      3 6. 0 0        1 0. 1 0                            2 6 5. 5      6 0 7 6.  
      4 8. 0 0        1 1. 0 0                            3 9 2. 1 1. 1 4 3 e + 0 0 4  
Pa ge 1 5 7 of 3 3 1
PI
PI


      6 0. 0 0        8. 9 7 0                            5 1 1. 5 1. 7 8 5 e + 0 0 4  
      7 2. 0 0        9. 8 9 0                            6 2 4. 6 2. 5 3 5 e + 0 0 4  
      9 6. 0 0        8. 4 3 0                            8 4 4. 0 4. 3 7 1 e + 0 0 4  
      1 2 0. 0 *      5. 5 5 0      5. 5 9 2   -0. 0 4 1 8 2      1 0 0 9. 6. 1 4 3 e + 0 0 4      1. 0 0 0  
      1 4 4. 0 *      3. 5 0 0      3. 4 4 8    0. 0 5 2 1 5      1 1 1 6. 7. 5 4 2 e + 0 0 4      1. 0 0 0  
      1 6 8. 0 *      2. 1 1 0      2. 1 2 6   -0. 0 1 5 9 0      1 1 8 2. 8. 5 6 3 e + 0 0 4      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 9 3  
R s q _ a dj u st e d                                              0. 9 9 8 6  
C orr _ X Y                                                  -0. 9 9 9 6  
N o _ p oi nt s _l a m b d a _ z                                        3  
L a m b d a _ z                                1/ h               0. 0 2 0 1  
L a m b d a _ z _l o w er                            h             1 2 0. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 4. 4 0 2 6  
Tl a g                                      h               1. 0 0 0 0  
T m a x                                      h              2 4. 0 1 6 7  
C m a x                                  n g/ m L              1 1. 3 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 0 2 5 1  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L               2. 1 1 0 0  
A U Cl a st                             h* n g/ m L            1 1 8 2. 0 0 0 3  
A U C all                              h* n g/ m L            1 1 8 2. 0 0 0 3  
A U CI N F _ o b s                          h* n g/ m L            1 2 8 6. 7 2 4 7  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g               2. 8 5 9 4  
A U C _ % E xtr a p _ o b s                           %               8. 1 3 8 8  
V z _ F _ o b s                                  L           1 7 3 5 7. 7 0 2 6  
Cl _ F _ o b s                                L/ h             3 4 9. 7 2 5 2  
A U CI N F _ pr e d                         h* n g/ m L            1 2 8 7. 5 1 3 8  
A U CI N F _ D _ pr e d                     h* n g/ m L/ m g               2. 8 6 1 1  
A U C _ % E xtr a p _ pr e d                          %               8. 1 9 5 1  
V z _ F _ pr e d                                 L           1 7 3 4 7. 0 6 4 4  
Cl _ F _ pr e d                               L/ h             3 4 9. 5 1 0 8  
A U M Cl a st                          h* h* n g/ m L           8 5 6 3 4. 6 5 5 3  
A U M CI N F _ o b s                       h* h* n g/ m L          1 0 8 4 2 6. 0 7 6 1  
A U M C _ % E xtr a p _ o b s                          %              2 1. 0 2 0 2  
A U M CI N F _ pr e d                      h* h* n g/ m L          1 0 8 5 9 7. 8 0 7 7  
A U M C _ % E xtr a p _ pr e d                         %              2 1. 1 4 5 1  
M R Tl a st                                   h              7 2. 4 4 8 9  
M R TI N F _ o b s                                h              8 4. 2 6 5 2  
M R TI N F _ pr e d                               h              8 4. 3 4 6 9  
A U C 0 _ 2 4                             h* n g/ m L             1 3 7. 1 9 0 1  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 5  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
Pa ge 1 5 8 of 3 3 1
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Summary T
able 
-------------  
      Time         Conc.      Pred.    Residual      AUC       AUMC      Weight
 
          h       ng/mL       ng/mL       ng/mL     h*ng/mL   h*h*ng/mL
 
-------------------------------------------------------------------------------
 
     0.0000       0.0000                           0.0000     0.0000 
     0.2500       0.0000                           
0.0000     0.0000 
     0.5000       0.0000                           0.0000     0.0000 
     0.7500       0.0000                           0.0000     0.0000 
      1.000       0.1350                          0.01688    0.01688 
      1.500       0.2780                           
0.1201     0.1549 
      2.000       0.6160                           0.3436     0.5671 
      3.000        1.530                            1.417      3.478 
      4.000        3.340                            3.852      12.45 
      6.000        4.640                            11.83      53.65 
      8.000        5.450                            21.92      125.1 
      12.00        5.540                            43.90      345.3 
      16.00        6.030                            67.04      671.2
 
      24.02        7.130                            119.8      1744.
 
      36.00        5.720                            196.5      4029.
 
      48.00        7.870                            278.0      7531.
 
      60.00        4.690                            
351.7 1.147e+004 
      72.00        4.550                            407.2 1.513e+004 
      96.00        4.170                            511.7 2.390e+004 
      120.0 *      3.110      3.039    0.07111      598.5 3.322e+004      1.000
 
      144.0 *      1.780      1.864   
-0.08425      655.7 4.070e+004      1.000
 
      168.0 *      1.170      1.143    0.02673      690.6 4.612e+004      1.000
 
 
 
*) Starred values were included in the estimation of Lambda_z.
 
 
 
Final Parameters
 
---------------  
R sq                                                       0.9933  
Rsq_adjusted                                              0.9867 
Corr_XY                                                  -0.9967
 
No_points_lambda_z                                        3
 
Lambda_z                                1/h               0.0204
 
Lambda_z_lower                            h             120.0167
 
Lambda_z_upper                            h             168.0000
 
HL_Lambda_z                               h              34.0215
 
Tlag                                      h               0.7500 
Tmax                                      h              48.0000 
Cmax                                  ng/mL               7.8700
 
Cmax_D                             ng/mL/mg               
0.0175 
Tlast                                     h             168.0000
 
Clast                                 ng/mL               1.1700 
AUClast                             h*ng/mL             690.5975 
AUCall                              h*ng/mL             
690.5975 
AUCINF_obs                          h*ng/mL             748.0242 
AUCINF_D_obs                     h*ng/mL/mg               1.6623 
AUC_%Extrap_obs                           %               7.6771 
Vz_F_obs                                  L      
     29527.3729
 
Cl_F_obs                                L/h             601.5848
 
AUCINF_pred                         h*ng/mL             746.7120 
AUCINF_D_pred                    h*ng/mL/mg               1.6594 
AUC_%Extrap_pred                          %               
7.5149 
Vz_F_pred                                 L           29579.2617
 
Cl_F_pred                               L/h             602.6420
 
AUMClast                          h*h*ng/mL           46117.0234 
AUMCINF_obs                       h*h*ng/mL           58583.3611 
AUMC_%Extrap_obs                          %              21.2797 
AUMCINF_pred                      h*h*ng/mL           58298.5043 
AUMC_%Extrap_pred                         %              20.8950 
MRTlast                              
     h              66.7784 
MRTINF_obs                                h              78.3175
 
MRTINF_pred                               h              78.0736
 
AUC0_24                             h*ng/mL             119.6725 
 
 
 
Page 159 of 331


Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 4  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0       0. 1 4 3 0                          0. 0 3 5 7 5    0. 0 5 3 6 3  
      2. 0 0 0       0. 4 1 1 0                           0. 1 7 4 3     0. 3 1 2 8  
      3. 0 0 0       0. 9 0 9 0                           0. 8 3 4 3      2. 0 8 7  
      4. 0 0 0        1. 6 5 0                            2. 1 1 4      6. 7 5 1  
      6. 0 1 7        2. 3 0 0                            6. 0 9 7      2 7. 3 6 
      8. 0 0 0        3. 1 1 0                            1 1. 4 6      6 5. 7 6  
      1 2. 0 0        4. 2 9 0                            2 6. 2 6      2 1 8. 5  
      1 6. 1 0        5. 7 9 0                            4 6. 9 3      5 1 5. 1  
      2 4. 0 7        7. 8 3 0                            1 0 1. 2      1 6 3 7.  
      3 6. 0 0        5. 9 5 0                            1 8 2. 9      4 0 6 9.  
      4 8. 0 0        6. 4 1 0                            2 5 7. 0      7 2 0 0.  
      6 0. 0 2        4. 1 9 0                            3 1 9. 8 1. 0 5 6 e + 0 0 4  
      7 2. 0 0 *      5. 1 5 0      5. 5 4 1    -0. 3 9 1 2      3 7 5. 8 1. 4 2 9 e + 0 0 4      1. 0 0 0  
      9 6. 1 7 *      3. 4 1 0      3. 2 4 1     0. 1 6 8 9      4 7 7. 7 2. 2 7 8 e + 0 0 4      1. 0 0 0  
      1 2 0. 0 *      1. 9 4 0      1. 9 1 0    0. 0 3 0 2 0      5 3 9. 9 2. 9 4 3 e + 0 0 4      1. 0 0 0  
      1 4 6. 9 *      1. 1 9 0      1. 0 5 1     0. 1 3 9 5      5 8 1. 2 3. 4 9 0 e + 0 0 4      1. 0 0 0  
      1 6 8. 0 *     0. 5 8 5 0     0. 6 5 8 2   -0. 0 7 3 2 2      5 9 9. 1 3. 7 7 0 e + 0 0 4      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 8 7 2  
R s q _ a dj u st e d                                              0. 9 8 2 9  
C orr _ X Y                                                  -0. 9 9 3 6  
N o _ p oi nt s _l a m b d a _ z                                        5  
L a m b d a _ z                                1/ h               0. 0 2 2 2  
L a m b d a _ z _l o w er                            h              7 2. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 1. 2 3 4 3  
Tl a g                                      h               1. 0 0 0 0  
T m a x                                      h              2 4. 0 6 6 7  
C m a x                                  n g/ m L               7. 8 3 0 0  
C m a x _ D                             n g/ m L/ m g               0. 0 1 7 4  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L               0. 5 8 5 0  
A U Cl a st                             h* n g/ m L             5 9 9. 1 4 3 5  
A U C all                              h* n g/ m L             5 9 9. 1 4 3 5  
Pa ge 1 6 0 of 3 3 1
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A U CI N F _ o b s                          h* n g/ m L             6 2 5. 5 0 4 5  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g               1. 3 9 0 0  
A U C _ % E xtr a p _ o b s                           %               4. 2 1 4 4  
V z _ F _ o b s                                  L           3 2 4 1 8. 1 1 9 3  
Cl _ F _ o b s                                L/ h             7 1 9. 4 1 9 3  
A U CI N F _ pr e d                         h* n g/ m L             6 2 8. 8 0 4 1  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g               1. 3 9 7 3  
A U C _ % E xtr a p _ pr e d                          %               4. 7 1 7 0  
V z _ F _ pr e d                                 L           3 2 2 4 8. 0 0 9 1  
Cl _ F _ pr e d                               L/ h             7 1 5. 6 4 4 2  
A U M Cl a st                          h* h* n g/ m L           3 7 7 0 1. 8 8 4 8  
A U M CI N F _ o b s                       h* h* n g/ m L           4 3 3 1 8. 3 9 5 5  
A U M C _ % E xtr a p _ o b s                          %              1 2. 9 6 5 6  
A U M CI N F _ pr e d                      h* h* n g/ m L           4 4 0 2 1. 4 0 7 7  
A U M C _ % E xtr a p _ pr e d                         %              1 4. 3 5 5 6  
M R Tl a st                                    h              6 2. 9 2 6 3  
M R TI N F _ o b s                                h              6 9. 2 5 3 5  
M R TI N F _ pr e d                               h              7 0. 0 0 8 1  
A U C 0 _ 2 4                             h* n g/ m L             1 0 0. 6 5 7 2  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 5  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M 
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 6 6 7       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 1 1 4 0                          0. 0 1 4 2 5    0. 0 1 4 2 5  
      1. 5 0 0       0. 3 8 9 0                           0. 1 4 0 0     0. 1 8 8 6  
      2. 0 0 0       0. 7 5 4 0                           0. 4 2 5 8     0. 7 1 1 5  
      3. 0 0 0        1. 5 0 0                            1. 5 5 3      3. 7 1 6  
      4. 0 0 0        2. 7 7 0                            3. 6 8 8      1 1. 5 1  
      6. 0 0 0        4. 1 8 0                            1 0. 6 4      4 7. 6 7  
      8. 0 0 0        7. 5 2 0                            2 2. 3 4      1 3 2. 9  
      1 2. 0 0        9. 0 7 0                            5 5. 5 2      4 7 0. 9  
      1 6. 0 0        1 2. 2 0                            9 8. 0 6      1 0 7 9.  
      2 4. 0 0        2 0. 4 0                            2 2 8. 5      3 8 1 8.  
      3 6. 0 0        1 3. 6 0                            4 2 9. 7      9 7 7 4.  
      4 8. 0 0        1 6. 2 0                            6 0 8. 5 1. 7 3 8 e + 0 0 4  
      6 0. 0 0        1 0. 2 0                            7 6 4. 1 2. 5 7 1 e + 0 0 4  
      7 2. 0 0 *      9. 9 4 0      9. 8 6 1    0. 0 7 8 5 9      8 8 5. 0 3. 3 6 8 e + 0 0 4      1. 0 0 0  
      9 6. 0 0 *      6. 4 1 0      6. 3 4 0    0. 0 6 9 5 2      1 0 7 8. 4. 9 7 3 e + 0 0 4      1. 0 0 0  
      1 2 0. 0 *      4. 1 6 0      4. 0 7 7    0. 0 8 3 3 4      1 2 0 3. 6. 3 1 2 e + 0 0 4      1. 0 0 0  
      1 4 4. 0 *      2. 3 6 0      2. 6 2 1    -0. 2 6 1 1      1 2 7 9. 7. 3 0 9 e + 0 0 4      1. 0 0 0  
      1 6 8. 0 *      1. 8 0 0      1. 6 8 5     0. 1 1 4 7      1 3 2 9. 8. 0 8 0 e + 0 0 4      1. 0 0 0  
 
Pa ge 1 6 1 of 3 3 1
PI
PI


 
*) St arr e d val u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z.  
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 1 9  
R s q _ a dj u st e d                                              0. 9 8 9 2  
C orr _ X Y                                                  -0. 9 9 5 9  
N o _ p oi nt s _l a m b d a _ z                                        5  
L a m b d a _ z                                1/ h               0. 0 1 8 4  
L a m b d a _ z _l o w er                            h              7 2. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 7. 6 6 4 6  
Tl a g                                      h               0. 7 5 0 0  
T m a x                                      h              2 4. 0 0 0 0  
C m a x                                  n g/ m L              2 0. 4 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 0 4 5 3  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L               1. 8 0 0 0  
A U Cl a st                             h* n g/ m L            1 3 2 8. 8 1 5 8  
A U C all                              h* n g/ m L            1 3 2 8. 8 1 5 8  
A U CI N F _ o b s                          h* n g/ m L            1 4 2 6. 6 2 5 1  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g               3. 1 7 0 3  
A U C _ % E xtr a p _ o b s                           %               6. 8 5 6 0  
V z _ F _ o b s                                  L           1 7 1 3 9. 9 7 8 2  
Cl _ F _ o b s                                L/ h             3 1 5. 4 2 9 8  
A U CI N F _ pr e d                         h* n g/ m L            1 4 2 0. 3 9 0 8  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g               3. 1 5 6 4  
A U C _ % E xtr a p _ pr e d                          %               6. 4 4 7 2  
V z _ F _ pr e d                                 L           1 7 2 1 5. 2 0 7 0  
Cl _ F _ pr e d                               L/ h             3 1 6. 8 1 4 2  
A U M Cl a st                          h* h* n g/ m L           8 0 8 0 3. 2 4 6 8  
A U M CI N F _ o b s                       h* h* n g/ m L          1 0 2 5 5 0. 0 1 7 1  
A U M C _ % E xtr a p _ o b s                          %              2 1. 2 0 6 0  
A U M CI N F _ pr e d                      h* h* n g/ m L          1 0 1 1 6 3. 9 1 1 7  
A U M C _ % E xtr a p _ pr e d                         %              2 0. 1 2 6 4  
M R Tl a st                                   h              6 0. 8 0 8 5  
M R TI N F _ o b s                                h              7 1. 8 8 2 9  
M R TI N F _ pr e d                               h              7 1. 2 2 2 6  
A U C 0 _ 2 4                             h* n g/ m L             2 2 8. 4 5 7 8  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 5  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
Pa ge 1 6 2 of 3 3 1
PI
PI


     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0       0. 1 9 1 0                          0. 0 4 7 7 5    0. 0 7 1 6 3  
      2. 0 0 0       0. 5 4 2 0                           0. 2 3 1 0     0. 4 1 4 3  
      3. 0 0 0        1. 1 9 0                            1. 0 9 7      2. 7 4 1  
      4. 0 0 0        2. 0 3 0                            2. 7 0 7      8. 5 8 6  
      6. 0 0 0        3. 6 1 0                            8. 3 4 7      3 8. 3 7  
      8. 0 1 7        4. 3 6 0                            1 6. 3 8      9 5. 4 5  
      1 2. 0 0        5. 2 7 0                            3 5. 5 6      2 9 1. 0  
      1 6. 0 0        6. 3 1 0                            5 8. 7 2      6 1 9. 4  
      2 4. 0 0        8. 5 2 0                            1 1 8. 0      1 8 4 1.  
      3 6. 0 0        6. 6 7 0                            2 0 8. 7      4 5 4 0.  
      4 8. 0 0        9. 4 4 0                            3 0 5. 4      8 6 9 9.  
      6 0. 0 3        7. 3 7 0                            4 0 6. 0 1. 4 1 1 e + 0 0 4  
      7 2. 0 0 *      7. 3 0 0      7. 0 7 5     0. 2 2 5 3      4 9 3. 8 1. 9 9 0 e + 0 0 4      1. 0 0 0  
      9 6. 0 3 *      4. 5 2 0      4. 6 0 3   -0. 0 8 2 6 3      6 3 3. 2 3. 1 4 8 e + 0 0 4      1. 0 0 0  
      1 2 0. 0 *      2. 9 4 0      2. 9 9 8   -0. 0 5 7 9 2      7 2 1. 2 4. 0 9 1 e + 0 0 4      1. 0 0 0  
      1 4 4. 0 *      1. 8 9 0      1. 9 5 2   -0. 0 6 1 5 3      7 7 8. 2 4. 8 3 9 e + 0 0 4      1. 0 0 0  
      1 6 8. 0 *      1. 3 2 0      1. 2 7 0    0. 0 4 9 6 3      8 1 6. 4 5. 4 3 1 e + 0 0 4      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 7 7  
R s q _ a dj u st e d                                              0. 9 9 7 0  
C orr _ X Y                                                  -0. 9 9 8 9  
N o _ p oi nt s _l a m b d a _ z                                        5  
L a m b d a _ z                                1/ h               0. 0 1 7 9  
L a m b d a _ z _l o w er                            h              7 2. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 8. 7 5 0 0  
Tl a g                                      h               1. 0 0 0 0  
T m a x                                      h              4 8. 0 0 0 0  
C m a x                                  n g/ m L               9. 4 4 0 0  
C m a x _ D                             n g/ m L/ m g               0. 0 2 1 0  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                  n g/ m L               1. 3 2 0 0  
A U Cl a st                             h* n g/ m L             8 1 6. 3 6 0 1  
A U C all                              h* n g/ m L             8 1 6. 3 6 0 1  
A U CI N F _ o b s                          h* n g/ m L             8 9 0. 1 5 3 9  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g               1. 9 7 8 1  
A U C _ % E xtr a p _ o b s                           %               8. 2 9 0 0  
V z _ F _ o b s                                  L           2 8 2 6 1. 3 9 0 9  
Cl _ F _ o b s                                L/ h             5 0 5. 5 3 0 6  
A U CI N F _ pr e d                         h* n g/ m L             8 8 7. 3 7 9 6  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g               1. 9 7 2 0  
A U C _ % E xtr a p _ pr e d                          %               8. 0 0 3 3  
V z _ F _ pr e d                                 L           2 8 3 4 9. 7 4 6 6  
Cl _ F _ p r e d                               L/ h             5 0 7. 1 1 1 0 
A U M Cl a st                          h* h* n g/ m L           5 4 3 1 1. 3 9 5 0  
A U M CI N F _ o b s                       h* h* n g/ m L           7 0 8 3 4. 1 5 9 6  
A U M C _ % E xtr a p _ o b s                          %              2 3. 3 2 6 0  
A U M CI N F _ pr e d                      h* h* n g/ m L           7 0 2 1 2. 9 8 5 8  
A U M C _ % E xtr a p _ pr e d                         %              2 2. 6 4 7 6  
M R Tl a st                                   h              6 6. 5 2 8 7  
M R TI N F _ o b s                                h              7 9. 5 7 5 2  
M R TI N F _ pr e d                               h              7 9. 1 2 4 0  
A U C 0 _ 2 4                             h* n g/ m L             1 1 8. 0 4 3 2  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 6  
 
 
Pa ge 1 6 3 of 3 3 1
PI
PI


                  WINNONLIN N
ONCOMPARTMENTAL ANALYSIS PROGRAM
 
                                   7.0.0.2535
 
                            Core Version 
04Jun2007 
 
Settings
 
--------  
Model:  Plasma Data, Extravascular Administration
 
Number of nonmissing observations:   22
 
Dose time:      0.00
 
Dose amount:      450.00
 
Calculation method:  Linear Trapezoidal Rule for for Increasing Values,
 
                     Log Trapezoidal Rule for Decreasing Values
 
Weighting for lambda_z calculations:  Uniform weighting
 
Lambda_z method:  Find best fit for lambda_z,  Log regression 
 
 
Summary Table 
-------------  
      Time         Conc.      Pred.    Residual      AUC       AUMC      Weight
 
          h       ng/mL       ng/mL       ng/mL     h*ng/mL   h*h*ng/mL
 
-------------------------------------------------------------------------------
 
     0.0000       0.0000                           0.0000     0.0000 
     0.2500       0.0000                           0.0000     0.0000 
     0.5000       0.0000                           0.0000     0.0000 
     0.7500       0.0000                           0.0000     0.0000 
      1.000       0.0000                           
0.0000     0.0000 
      1.500       0.0000                           0.0000     0.0000 
      2.000       0.0000                           0.0000     0.0000 
      3.000       0.2140                           0.1070     0.3210 
      4.000       0.4830    
                       0.4555      1.608 
      6.000        1.430                            2.369      12.12 
      8.000        1.830                            5.629      35.34 
      12.00        2.090                            13.47      114.8 
      16.00        2.710                            23.07      251.7 
      24.00        4.090                            50.27      817.7 
      36.00        3.480                            95.59      2170.
 
      48.00 *      3.770      3.808   
-0.03767      139.1      
4008.      1.000 
      60.00 *      2.700      2.943    
-0.2426      177.6      6072.      1.000 
      72.00 *      2.350      2.274    0.07593      207.8      8064.      1.000 
      96.00 *      1.580      
1.358     0.2219      254.4 1.194e+004      1.000
 
      120.0 *     0.7180     0.8111   
-0.09313      280.6 1.473e+004      1.000
 
      144.0 *     0.5330     0.4844    0.04856      295.5 1.669e+004      1.000
 
      168.0 *     0.2720     0.2893   
-0.01732      304.8 1.813e+004      1.000
 
 
 
*) Starred values were included in the estimation of Lambda_z.
 
 
 
Final Parameters
 
---------------  
Rsq                                                       0.9895  
Rsq_adjusted                                              0.9873 
Corr_XY                                                  -0.9947
 
No_points_lambda_z                                        7
 
Lambda_z                                1/h               0.0215
 
Lambda_z_lower                            h              48.0000
 
Lambda_z_upper                            h             168.0000
 
HL_Lambda_z                               h              32.2740
 
Tlag                                      h               2.0000 
Tmax                                      h              24.0000 
Cmax                                  ng/mL               4.0900
 
Cmax_D                             ng/mL/mg               0.0091 
Tlast                                     h             168.0000
 
Clast                                 ng/mL               
0.2720 
AUClast                             h*ng/mL             304.7987 
AUCall                              h*ng/mL             304.7987 
AUCINF_obs                          h*ng/mL             317.4634 
AUCINF_D_obs                     h*ng/mL/mg               0.7055 
AUC_%Extrap_obs                           %               3.9894 
Vz_F_obs                                  L           66000.3644
 
Cl_F_obs                                L/h            1417.4861
 
AUCINF_pred                         h*ng/mL             318.2699 
AUCINF_D_pred                    h*ng/mL/mg               0.7073 
Page 164 of 331


A U C _ % E xtr a p _ pr e d                          %               4. 2 3 2 7  
V z _ F _ pr e d                                 L           6 5 8 3 3. 1 1 4 6  
Cl _ F _ pr e d                               L/ h            1 4 1 3. 8 9 4 1  
A U M Cl a st                          h* h* n g/ m L           1 8 1 2 7. 7 1 5 3  
A U M CI N F _ o b s                       h* h* n g/ m L           2 0 8 4 5. 0 8 2 6  
A U M C _ % E xtr a p _ o b s                          %              1 3. 0 3 6 0  
A U M CI N F _ pr e d                      h* h* n g/ m L           2 1 0 1 8. 1 3 0 7  
A U M C _ % E xtr a p _ pr e d                         %              1 3. 7 5 2 0  
M R Tl a st                                   h              5 9. 4 7 4 4  
M R TI N F _ o b s                                h              6 5. 6 6 1 4  
M R TI N F _ pr e d                               h              6 6. 0 3 8 7  
A U C 0 _ 2 4                             h* n g/ m L              5 0. 2 6 8 5  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 6  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 8 1 6 7       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 1 7       0. 1 0 8 0                          0. 0 1 0 8 0    0. 0 1 0 9 8  
      1. 5 0 0       0. 2 2 3 0                          0. 0 9 0 7 9     0. 1 1 8 4  
      2. 0 0 0       0. 4 2 4 0                           0. 2 5 2 5     0. 4 1 4 0  
      3. 0 0 0        1. 3 9 0                            1. 1 6 0      2. 9 2 3  
      4. 0 0 0        2. 4 5 0                            3. 0 8 0      9. 9 0 8  
      6. 0 0 0        3. 2 9 0                            8. 8 2 0      3 9. 4 5  
      8. 0 3 3        4. 4 6 0                            1 6. 7 0      9 5. 9 4  
      1 2. 0 0        4. 6 8 0                            3 4. 8 3      2 7 8. 4  
      1 6. 0 0        5. 8 6 0                            5 5. 9 1      5 7 8. 2  
      2 4. 0 0        5. 9 5 0                            1 0 3. 1      1 5 2 4.  
      3 6. 0 0        4. 5 4 0                            1 6 5. 7      3 3 8 4.  
      4 8. 0 2        4. 3 2 0                            2 1 8. 9      5 6 1 7.  
      6 0. 0 8        3. 1 2 0                            2 6 3. 4      8 0 0 8.  
      7 2. 0 0        2. 1 4 0                            2 9 4. 4 1. 0 0 4 e + 0 0 4  
      9 5. 7 3 *      1. 3 2 0      1. 3 2 0  0. 0 0 0 3 1 0 4      3 3 4. 7 1. 3 3 8 e + 0 0 4      1. 0 0 0 
      1 2 0. 1 *     0. 8 9 4 0     0. 8 9 2 7   0. 0 0 1 3 0 3      3 6 1. 4 1. 6 2 4 e + 0 0 4      1. 0 0 0  
      1 4 4. 0 *      0. 6 0 7 0     0. 6 0 9 0  -0. 0 0 2 0 4 1      3 7 9. 0 1. 8 5 6 e + 0 0 4      1. 0 0 0  
      1 7 1. 8 *      0. 3 9 1 0     0. 3 9 0 4  0. 0 0 0 6 4 9 7      3 9 2. 7 2. 0 7 0 e + 0 0 4      1. 0 0 0  
 
 
*) St arr e d val u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z.  
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       1. 0 0 0 0  
Pa ge 1 6 5 of 3 3 1
PI
PI


R s q _ a dj u st e d                                              1. 0 0 0 0  
C orr _ X Y                                                  -1. 0 0 0 0  
N o _ p oi nt s _l a m b d a _ z                                        4  
L a m b d a _ z                                1/ h               0. 0 1 6 0  
L a m b d a _ z _l o w er                            h              9 5. 7 3 3 3  
L a m b d a _ z _ u p p er                            h             1 7 1. 7 6 6 7  
H L _ L a m b d a _ z                               h              4 3. 2 6 5 7  
Tl a g                                      h               0. 8 1 6 7  
T m a x                                      h              2 4. 0 0 0 0  
C m a x                                  n g/ m L               5. 9 5 0 0  
C m a x _ D                             n g/ m L/ m g               0. 0 1 3 2  
Tl a st                                     h             1 7 1. 7 6 6 7  
Cl a st                                 n g/ m L               0. 3 9 1 0  
A U Cl a st                             h* n g/ m L             3 9 2. 6 7 9 3  
A U C all                              h* n g/ m L             3 9 2. 6 7 9 3  
A U CI N F _ o b s                          h* n g/ m L             4 1 7. 0 8 5 2  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g               0. 9 2 6 9  
A U C _ % E xtr a p _ o b s                           %               5. 8 5 1 5  
V z _ F _ o b s                                  L           6 7 3 4 5. 1 3 3 1  
Cl _ F _ o b s                                L/ h            1 0 7 8. 9 1 6 2  
A U CI N F _ pr e d                         h* n g/ m L             4 1 7. 0 4 4 7  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g               0. 9 2 6 8  
A U C _ % E xtr a p _ pr e d                          %               5. 8 4 2 4  
V z _ F _ pr e d                                 L           6 7 3 5 1. 6 8 1 7  
Cl _ F _ pr e d                               L/ h            1 0 7 9. 0 2 1 1  
A U M Cl a st                          h* h* n g/ m L           2 0 7 0 1. 6 2 1 7  
A U M CI N F _ o b s                       h* h* n g/ m L           2 6 4 1 7. 1 4 5 4  
A U M C _ % E xtr a p _ o b s                          %              2 1. 6 3 5 7  
A U M CI N F _ pr e d                      h* h* n g/ m L           2 6 4 0 7. 6 4 8 5  
A U M C _ % E xtr a p _ pr e d                         %              2 1. 6 0 7 5  
M R Tl a st                                   h              5 2. 7 1 8 9  
M R TI N F _ o b s                                h              6 3. 3 3 7 5  
M R TI N F _ pr e d                               h              6 3. 3 2 0 9  
A U C 0 _ 2 4                             h* n g/ m L             1 0 3. 1 4 6 4  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 4  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   1 8  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     Lo g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 1 3 1 0                          0. 0 1 6 3 8    0. 0 1 6 3 8  
      1. 5 0 0       0. 2 1 2 0                           0. 1 0 2 1     0. 1 2 8 6  
      2. 0 0 0       0. 3 4 3 0                           0. 2 4 0 9     0. 3 7 9 6  
      3. 0 0 0        1. 2 5 0                            1. 0 3 7      2. 5 9 8  
Pa ge 1 6 6 of 3 3 1
PI
PI


      4. 0 0 0        2. 3 6 0                            2. 8 4 2      9. 1 9 3  
      6. 0 0 0        3. 5 4 0                            8. 7 4 2      3 9. 8 7  
      8. 0 0 0        4. 8 7 0                            1 7. 1 5      1 0 0. 1  
      1 2. 0 0        4. 9 9 0                            3 6. 8 7      2 9 7. 8  
      1 6. 0 0        5. 5 6 0                            5 7. 9 7      5 9 5. 4  
      2 4. 0 0        6. 1 1 0                            1 0 4. 7      1 5 3 8.  
      3 6. 0 0 *      4. 4 7 0      4. 5 2 7   -0. 0 5 6 6 6      1 6 7. 6      3 4 0 7.      1. 0 0 0  
      4 8. 0 0 *      3. 7 9 0      3. 5 4 8     0. 2 4 2 3      2 1 7. 1      5 4 7 6.       1. 0 0 0  
      6 0. 0 0 *      2. 5 3 0      2. 7 8 0    -0. 2 5 0 4      2 5 4. 5      7 4 8 1.      1. 0 0 0  
      7 2. 0 0 *      2. 2 7 0      2. 1 7 9    0. 0 9 0 9 4      2 8 3. 3      9 3 7 7.      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 5 1 6  
R s q _ a dj u st e d                                              0. 9 2 7 4  
C orr _ X Y                                                  -0. 9 7 5 5  
N o _ p oi nt s _l a m b d a _ z                                        4  
L a m b d a _ z                                1/ h               0. 0 2 0 3  
L a m b d a _ z _l o w er                            h              3 6. 0 0 0 0  
L a m b d a _ z _ u p p er                            h              7 2. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 4. 1 3 1 6  
Tl a g                                      h               0. 7 5 0 0  
T m a x                                      h              2 4. 0 0 0 0  
C m a x                                  n g/ m L               6. 1 1 0 0  
C m a x _ D                             n g/ m L/ m g               0. 0 1 3 6  
Tl a st                                     h              7 2. 0 0 0 0  
Cl a st                                 n g/ m L               2. 2 7 0 0  
A U Cl a st                             h* n g/ m L             2 8 3. 2 5 2 4  
A U C all                              h* n g/ m L             2 8 3. 2 5 2 4  
A U CI N F _ o b s                          h* n g/ m L             3 9 5. 0 3 0 5  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g               0. 8 7 7 8  
A U C _ % E xtr a p _ o b s                           %              2 8. 2 9 6 1  
V z _ F _ o b s                                  L           5 6 0 9 3. 4 9 8 5  
Cl _ F _ o b s                                L/ h            1 1 3 9. 1 5 2 6  
A U CI N F _ pr e d                         h* n g/ m L             3 9 0. 5 5 2 4  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g               0. 8 6 7 9  
A U C _ % E xtr a p _ pr e d                          %              2 7. 4 7 3 9  
V z _ F _ pr e d                                 L           5 6 7 3 6. 6 7 4 7  
Cl _ F _ pr e d                               L/ h            1 1 5 2. 2 1 4 3  
A U M Cl a st                          h* h* n g/ m L            9 3 7 6. 8 8 3 1  
A U M CI N F _ o b s                       h* h* n g/ m L           2 2 9 2 9. 0 1 1 9  
A U M C _ % E xtr a p _ o b s                          %              5 9. 1 0 4 7  
A U M CI N F _ pr e d                      h* h* n g/ m L           2 2 3 8 6. 0 7 7 0  
A U M C _ % E xtr a p _ pr e d                         %              5 8. 1 1 2 9  
M R Tl a st                                   h              3 3. 1 0 4 3  
M R TI N F _ o b s                                h              5 8. 0 4 3 7  
M R TI N F _ pr e d                               h              5 7. 3 1 9 0  
A U C 0 _ 2 4                             h* n g/ m L             1 0 4. 6 5 2 4  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 6  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:   Pl a s m a D at a,  E xtr a v a s c u l ar A d mi ni str ati o n 
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
Pa ge 1 6 7 of 3 3 1
PI
PI


                     Log Trapezoidal R
ule for Decreasing Values
 
Weighting for lambda_z calculations:  Uniform weighting
 
Lambda_z method:  Find best fit for lambda_z,  Log regression 
 
 
Summary Table 
-------------  
      Time         Conc.      Pred.    Residual      AUC       AUMC      Weight
 
          h       ng/mL       
ng/mL       ng/mL     h*ng/mL   h*h*ng/mL
 
-------------------------------------------------------------------------------
 
     0.0000       0.0000                           0.0000     0.0000 
     0.2500       0.0000                           0.0000     0.0000 
     0.5000       0.0000                           0.0000     0.0000 
     0.7500       0.1190                          0.01488    0.01116 
      1.017       0.1210                          0.04688    0.03946 
      1.500       0.2980                   
        0.1481     0.1772 
      2.000       0.6780                           0.3921     0.6280 
      3.000        1.570                            1.516      3.661 
      4.000        2.790                            3.696      11.60 
      6.000        4.260                            10.75      48.32 
      8.000        5.560                            20.57      118.4 
      12.00        5.900                            43.49      348.9 
      16.00        7.180                            69.65      720.3 
      24.02        9.170                            135.2      2064.
 
      36.00        7.880                            237.1      5108.
 
      48.00        8.560                            335.8      9275.
 
      60.00        5.610                            419.6 1.376e+004 
      72.00 *      6.040      6.006    0.03375      489.5 1.839e+004      1.000
 
      96.00 *      4.040      3.847     0.1926      608.8 2.832e+004      1.000
 
      120.0 *      2.370   
   2.463   
-0.09296      684.1 3.637e+004      1.000
 
      144.0 *      1.440      1.579    
-0.1387      728.8 4.223e+004      1.000
 
      168.1 *      1.090      1.010    0.07971      759.0 4.693e+004      1.000
 
 
 
*) Starred values were included in the estimation of Lambda_z.
 
 
 
Final Parameters
 
---------------  
Rsq                                                       0.9910  
Rsq_adjusted                                              0.9879 
Corr_XY                                                  -0.9955
 
No_p
oints_lambda_z                                        5
 
Lambda_z                                1/h               0.0186
 
Lambda_z_lower                            h              72.0000
 
Lambda_z_upper                            h             168.0500
 
HL_Lambda_z                               h              37.3489
 
Tlag                                      h               0.5000 
Tmax                                      h              24.0167 
Cmax                                  ng/mL               9.1700
 
C max_D                             ng/mL/mg               0.0204 
Tlast                                     h             168.0500
 
Clast                                 ng/mL               1.0900 
AUClast                             h*ng/mL             759.0323 
AUCall                              h*ng/mL             759.0323 
AUCINF_obs                          h*ng/mL             817.7648 
AUCINF_D_obs                     h*ng/mL/mg               1.8173 
AUC_%Extrap_obs                           %               7.1821 
Vz_F_obs                                  L           29650.7724
 
Cl_F_obs                                L/h             550.2805
 
AUCINF_pred                         h*ng/mL             813.4696
 
AUCINF_D_pred                    h*ng/mL/mg               1.8077 
AUC_%Extrap_pred                          %               6.6920 
Vz_F_pred                                 L           29807.3303
 
Cl_F_pred                               L/h             553.1860
 
AUMClast                          h*h*ng/mL           46932.1780 
AUMCINF_obs                       h*h*ng/mL           59966.8564 
AUMC_%Extrap_obs                          %              21.7365 
AUMCINF_pred                      h*h*ng/mL           
59013.6162 
AUMC_%Extrap_pred                         %              20.4723 
MRTlast                                   h              61.8316 
MRTINF_obs                                h              73.3302
 
MRTINF_pred                               h              
72.5456
 
Page 168 of 331


A U C 0 _ 2 4                             h* n g/ m L             1 3 5. 0 2 9 6  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 6  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0       0. 1 8 6 0                          0. 0 4 6 5 0    0. 0 6 9 7 5  
      2. 0 0 0       0. 3 5 3 0                           0. 1 8 1 3     0. 3 1 6 0  
      3. 0 0 0       0. 9 7 3 0                           0. 8 4 4 3      2. 1 2 9  
      4. 0 0 0        1. 8 5 0                            2. 2 5 6      7. 2 8 8  
      6. 0 0 0        3. 2 1 0                            7. 3 1 6      3 3. 9 5  
      8. 0 0 0        4. 1 8 0                            1 4. 7 1      8 6. 6 5  
      1 2. 0 0        4. 8 1 0                            3 2. 6 9      2 6 9. 0  
      1 6. 0 0        5. 1 8 0                            5 2. 6 7      5 5 0. 2  
      2 4. 0 0        6. 5 6 0                            9 9. 6 3      1 5 1 1.  
      3 6. 0 0        4. 4 9 0                            1 6 5. 1      3 4 5 2.  
      4 8. 0 0 *      4. 8 2 0      4. 6 5 8     0. 1 6 2 2      2 2 1. 0      5 8 1 0.      1. 0 0 0 
      6 0. 0 0 *      3. 2 1 0      3. 5 3 2    -0. 3 2 1 6      2 6 8. 5      8 3 5 7.      1. 0 0 0  
      7 2. 0 0 *      2. 7 3 0      2. 6 7 8    0. 0 5 2 3 1      3 0 4. 1 1. 0 7 0 e + 0 0 4      1. 0 0 0  
      9 6. 0 0 *      1. 6 8 0      1. 5 3 9     0. 1 4 0 6      3 5 6. 0 1. 5 0 1 e + 0 0 4      1. 0 0 0  
      1 2 0. 0 *     0. 8 0 0 0     0. 8 8 5 0   -0. 0 8 4 9 6      3 8 4. 5 1. 8 0 4 e + 0 0 4      1. 0 0 0  
      1 4 4. 0 *     0. 5 7 4 0     0. 5 0 8 8    0. 0 6 5 2 4      4 0 0. 8 2. 0 1 9 e + 0 0 4      1. 0 0 0  
      1 6 8. 0 *     0. 2 7 4 0     0. 2 9 2 5   -0. 0 1 8 4 8      4 1 0. 5 2. 1 6 9 e + 0 0 4      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 2 7  
R s q _ a dj u st e d                                              0. 9 9 1 2  
C orr _ X Y                                                  -0. 9 9 6 3  
N o _ p oi nt s _l a m b d a _ z                                        7  
L a m b d a _ z                                1/ h               0. 0 2 3 1  
L a m b d a _ z _l o w er                            h              4 8. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 0. 0 5 0 8  
Tl a g                                      h               1. 0 0 0 0  
T m a x                                      h              2 4. 0 0 0 0  
C m a x                                  n g/ m L               6. 5 6 0 0  
C m a x _ D                             n g/ m L/ m g               0. 0 1 4 6  
Pa ge 1 6 9 of 3 3 1
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PI


Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L               0. 2 7 4 0  
A U Cl a st                             h* n g/ m L             4 1 0. 5 3 7 4  
A U C all                              h* n g/ m L             4 1 0. 5 3 7 4  
A U CI N F _ o b s                          h* n g/ m L             4 2 2. 4 1 6 4  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g               0. 9 3 8 7  
A U C _ % E xtr a p _ o b s                           %               2. 8 1 2 2  
V z _ F _ o b s                                  L           4 6 1 8 5. 1 0 5 3  
Cl _ F _ o b s                                L/ h            1 0 6 5. 2 9 9 6  
A U CI N F _ pr e d                         h* n g/ m L             4 2 3. 2 1 7 4  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g               0. 9 4 0 5  
A U C _ % E xtr a p _ pr e d                          %               2. 9 9 6 1  
V z _ F _ pr e d                                 L           4 6 0 9 7. 6 8 7 1  
Cl _ F _ pr e d                               L/ h            1 0 6 3. 2 8 3 2  
A U M Cl a st                           h* h* n g/ m L           2 1 6 9 1. 3 8 9 1  
A U M CI N F _ o b s                       h* h* n g/ m L           2 4 2 0 2. 0 6 9 5  
A U M C _ % E xtr a p _ o b s                          %              1 0. 3 7 3 8  
A U M CI N F _ pr e d                      h* h* n g/ m L           2 4 3 7 1. 3 7 6 1  
A U M C _ % E xtr a p _ pr e d                         %              1 0. 9 9 6 5  
M R Tl a st                                   h              5 2. 8 3 6 6  
M R TI N F _ o b s                                h              5 7. 2 9 4 3  
M R TI N F _ pr e d                               h              5 7. 5 8 5 9  
A U C 0 _ 2 4                             h* n g/ m L              9 9. 6 2 5 8  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 4  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m  w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 5 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      2. 0 1 7       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      3. 0 0 0       0. 2 5 4 0                           0. 1 2 4 9     0. 3 7 4 6  
      4. 0 0 0       0. 4 6 3 0                           0. 4 8 3 4      1. 6 8 2  
      6. 0 0 0       0. 9 9 7 0                            1. 9 4 3      9. 5 1 6  
      8. 0 0 0        1. 8 8 0                            4. 8 2 0      3 0. 5 4  
      1 2. 0 0        3. 4 4 0                            1 5. 4 6      1 4 3. 2  
      1 6. 0 0        5. 3 8 0                            3 3. 1 0      3 9 7. 9  
      2 4. 0 0        8. 5 4 0                            8 8. 7 8      1 5 6 2.  
      3 6. 0 0        7. 5 1 0                            1 8 4. 9      4 4 3 5.  
      4 8. 0 0        8. 3 4 0                            2 8 0. 0      8 4 5 9.  
      6 0. 0 0        5. 2 3 0                            3 6 0. 0 1. 2 7 4 e + 0 0 4  
      7 2. 0 0 *      5. 1 5 0      5. 4 4 4    -0. 2 9 4 4      4 2 2. 3 1. 6 8 5 e + 0 0 4      1. 0 0 0  
      9 6. 0 7 *      3. 5 8 0      3. 4 8 4    0. 0 9 6 2 2      5 2 6. 2 2. 5 5 1 e + 0 0 4      1. 0 0 0  
Pa ge 1 7 0 of 3 3 1
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PI


      1 2 0. 0 *      2. 3 0 0      2. 2 3 5    0. 0 6 5 2 6      5 9 5. 4 3. 2 9 2 e + 0 0 4      1. 0 0 0  
      1 4 4. 1 *       1. 5 5 0      1. 4 2 9     0. 1 2 1 4      6 4 1. 3 3. 8 9 4 e + 0 0 4      1. 0 0 0  
      1 6 8. 6 *     0. 8 3 6 0     0. 9 0 7 4   -0. 0 7 1 4 1      6 6 9. 6 4. 3 3 3 e + 0 0 4      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 1 1  
R s q _ a dj u st e d                                              0. 9 8 8 1  
C orr _ X Y                                                  -0. 9 9 5 5  
N o _ p oi nt s _l a m b d a _ z                                        5 
L a m b d a _ z                                1/ h               0. 0 1 8 6  
L a m b d a _ z _l o w er                            h              7 2. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 5 8 3 3  
H L _ L a m b d a _ z                               h              3 7. 3 6 3 9  
Tl a g                                      h               2. 0 1 6 7  
T m a x                                      h              2 4. 0 0 0 0  
C m a x                                  n g/ m L               8. 5 4 0 0  
C m a x _ D                             n g/ m L/ m g               0. 0 1 9 0  
Tl a st                                     h             1 6 8. 5 8 3 3  
Cl a st                                 n g/ m L               0. 8 3 6 0  
A U Cl a st                             h* n g/ m L             6 6 9. 5 7 4 3  
A U C all                              h* n g/ m L             6 6 9. 5 7 4 3  
A U CI N F _ o b s                          h* n g/ m L             7 1 4. 6 3 8 6  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g               1. 5 8 8 1  
A U C _ % E xtr a p _ o b s                           %               6. 3 0 5 9  
V z _ F _ o b s                                  L           3 3 9 4 3. 1 7 3 3  
Cl _ F _ o b s                                L/ h             6 2 9. 6 8 8 9  
A U CI N F _ pr e d                         h* n g/ m L             7 1 8. 4 8 8 1  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g               1. 5 9 6 6  
A U C _ % E xtr a p _ pr e d                          %               6. 8 0 7 9  
V z _ F _ pr e d                                 L           3 3 7 6 1. 3 1 5 7  
Cl _ F _ pr e d                               L/ h             6 2 6. 3 1 5 2  
A U M Cl a st                          h* h* n g/ m L           4 3 3 2 9. 7 2 2 0  
A U M CI N F _ o b s                       h* h* n g/ m L           5 3 3 5 5. 9 8 9 6  
A U M C _ % E xtr a p _ o b s                          %              1 8. 7 9 1 3  
A U M CI N F _ pr e d                      h* h* n g/ m L           5 4 2 1 2. 4 4 5 9  
A U M C _ % E xtr a p _ pr e d                         %              2 0. 0 7 4 2  
M R Tl a st                                   h              6 4. 7 1 2 3  
M R TI N F _ o b s                                h              7 4. 6 6 1 5  
M R TI N F _ pr e d                               h              7 5. 4 5 3 5  
A U C 0 _ 2 4                             h* n g/ m L              8 8. 7 8 0 4  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 5  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
Pa ge 1 7 1 of 3 3 1
PI
PI


      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 6 6 7       0. 1 0 7 0                          0. 0 1 4 2 7    0. 0 1 0 9 4  
      1. 0 0 0       0. 2 2 8 0                          0. 0 5 3 3 5    0. 0 4 7 1 1  
      1. 5 0 0       0. 6 6 3 0                           0. 2 7 6 1     0. 3 5 2 7  
      2. 0 0 0        1. 2 3 0                           0. 7 4 9 4      1. 2 1 6  
      3. 0 0 0        2. 3 2 0                            2. 5 2 4      5. 9 2 6  
      4. 0 0 0        3. 3 5 0                            5. 3 5 9      1 6. 1 1  
      6. 0 0 0        4. 1 7 0                            1 2. 8 8      5 4. 5 3  
      8. 0 1 7        5. 5 7 0                            2 2. 7 0      1 2 4. 8  
      1 2. 0 0        6. 4 9 0                            4 6. 7 2      3 6 8. 8  
      1 6. 0 0        8. 3 8 0                            7 6. 4 6      7 9 2. 7  
      2 4. 0 2        1 2. 8 0                            1 6 1. 4      2 5 6 2.  
      3 6. 0 0        8. 2 5 0                            2 8 5. 5      6 2 3 3.  
      4 8. 0 0        8. 2 3 0                            3 8 4. 4 1. 0 3 9 e + 0 0 4  
      6 0. 0 0        5. 0 3 0                            4 6 2. 4 1. 4 5 6 e + 0 0 4  
      7 2. 0 0 *      5. 4 8 0      5. 4 9 7   -0. 0 1 6 7 9      5 2 5. 4 1. 8 7 4 e + 0 0 4      1. 0 0 0  
      9 6. 0 0 *      3. 8 4 0      3. 6 2 3     0. 2 1 7 4      6 3 6. 1 2. 7 9 6 e + 0 0 4      1. 0 0 0  
      1 2 0. 0 *      2. 1 3 0      2. 3 8 7    -0. 2 5 7 4      7 0 5. 7 3. 5 3 9 e + 0 0 4      1. 0 0 0  
      1 4 4. 0 *      1. 6 8 0      1. 5 7 3     0. 1 0 6 6      7 5 1. 2 4. 1 3 8 e + 0 0 4      1. 0 0 0  
      1 6 8. 0 *      1. 0 3 0      1. 0 3 7  -0. 0 0 6 9 2 1      7 8 3. 1 4. 6 3 2 e + 0 0 4      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 8 8 2  
R s q _ a dj u st e d                                              0. 9 8 4 3  
C orr _ X Y                                                  -0. 9 9 4 1  
N o _ p oi nt s _l a m b d a _ z                                        5  
L a m b d a _ z                                1/ h               0. 0 1 7 4  
L a m b d a _ z _l o w er                            h              7 2. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 9. 8 9 5 6  
Tl a g                                      h               0. 5 0 0 0  
T m a x                                      h              2 4. 0 1 6 7  
C m a x                                  n g/ m L              1 2. 8 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 0 2 8 4  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L               1. 0 3 0 0  
A U Cl a st                             h* n g/ m L             7 8 3. 1 2 7 6  
A U C all                              h* n g/ m L             7 8 3. 1 2 7 6  
A U CI N F _ o b s                          h* n g/ m L             8 4 2. 4 1 1 4  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g               1. 8 7 2 0  
A U C _ % E xtr a p _ o b s                           %               7. 0 3 7 4  
V z _ F _ o b s                                  L           3 0 7 4 5. 9 0 6 6  
Cl _ F _ o b s                                L/ h             5 3 4. 1 8 0 8  
A U CI N F _ pr e d                         h* n g/ m L             8 4 2. 8 0 9 8  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g               1. 8 7 2 9  
A U C _ % E xtr a p _ pr e d                          %               7. 0 8 1 3  
V z _ F _ pr e d                                 L           3 0 7 3 1. 3 7 3 7  
Cl _ F _ pr e d                               L/ h             5 3 3. 9 2 8 3  
A U M Cl a st                          h* h* n g/ m L           4 6 3 2 3. 1 6 6 1  
A U M CI N F _ o b s                       h* h* n g/ m L           5 9 6 9 5. 0 5 5 5  
A U M C _ % E xtr a p _ o b s                          %              2 2. 4 0 0 3  
A U M CI N F _ pr e d                      h* h* n g/ m L           5 9 7 8 4. 9 1 2 6  
A U M C _ % E xtr a p _ pr e d                         %              2 2. 5 1 7 0  
M R Tl a st                                    h              5 9. 1 5 1 5  
M R TI N F _ o b s                                h              7 0. 8 6 2 1  
M R TI N F _ pr e d                               h              7 0. 9 3 5 2  
A U C 0 _ 2 4                             h* n g/ m L             1 6 1. 1 4 3 3  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
Pa ge 1 7 2 of 3 3 1
PI


                                                  
Date:    
 
                                                  
Time:     09:27:24 
 
 
                  WINNONLIN NONCOMPARTMENTAL ANALY
SIS PROGRAM
 
                                   7.0.0.2535
 
                            Core Version 04Jun2007 
 
Settings
 
--------  
Model:  Plasma Data, Extravascular Administration
 
Number of nonmissing observations:   22
 
Dose time:      0.00
 
Dose amount:      
450.00
 
Calculation method:  Linear Trapezoidal Rule for for Increasing Values,
 
                     Log Trapezoidal Rule for Decreasing Values
 
Weighting for lambda_z calculations:  Uniform weighting
 
Lambda_z method:  Find best fit for lambda_z,  Log regression
 
 
 
Summary Table 
-------------  
      Time         Conc.      Pred.    Residual      AUC       AUMC      Weight
 
          h       ng/mL       ng/mL       ng/mL     h*ng/mL   h*h*ng/mL
 
-------------------------------------------------------------------------------
 
     0.0000       0.0000                           0.0000     0.0000 
     0.2500       0.0000                           0.0000     0.0000 
     0.5000       0.0000                           0.0000     0.0000 
     0.7500       0.0000                           0.0000     0.0000 
      1.033       0.0000                           0.0000     0.0000 
      1.500       0.1360                          0.03173    0.04760 
      2.000       0.2340                         
  0.1242     0.2156 
      3.000       0.6010                           0.5417      1.351 
      4.000        1.060                            1.372      4.373 
      6.000        3.630                            6.062      30.39 
      8.000        5.020                            
14.71      92.33 
      12.00        6.010                            36.77      316.9 
      16.00        5.960                            60.71      652.0 
      24.00        8.360                            118.0      1836.
 
      36. 00        6.850                            209.0      4547.
 
      48.02        6.330                            288.1      7865.
 
      60.00        4.670                            353.5 1.138e+004 
      72.00        4.290                            407.2 1.492e+004 
      96.00 *      3.350      3.375   
-0.02456      498.4 2.254e+004      1.000
 
      120.0 *      2.140      2.141  
-0.001094      563.2 2.948e+004      1.000
 
      144.0 *      1.390      1.358    0.03152      605.0 3.495e+004      1.000
 
      168.0 *     0.8490     0.8619   
-0.01293      631.3 3.903e+004      1.000
 
 
 
*) Starred values were included in the estimation of Lambda_z.
 
 
 
Final Parameters
 
---------------  
Rsq                                                       0.9992  
Rsq_adjusted                                              0.9988 
Corr_XY                                                  -0.9996
 
No_points_lambda_z                                        4
 
Lambda_z                                1/h               0.0190
 
L ambda_z_lower                            h              96.0000
 
Lambda_z_upper                            h             168.0000
 
HL_Lambda_z                               h              36.5659
 
Tlag                                      h               1.03 33 
Tmax                                      h              24.0000 
Cmax                                  ng/mL               8.3600
 
Cmax_D                             ng/mL/mg               0.0186 
Tlast                                     h             16 8.0000
 
Clast                                 ng/mL               0.8490 
AUClast                             h*ng/mL             631.2989 
AUCall                              h*ng/mL             631.2989 
AUCINF_obs                          h*ng/mL             
676.0866 
AUCINF_D_obs                     h*ng/mL/mg               1.5024 
AUC_%Extrap_obs                           %               6.6245 
Page 173 of 331
PI


V z _ F _ o b s                                  L           3 5 1 1 2. 3 9 9 3  
Cl _ F _ o b s                                L/ h             6 6 5. 5 9 5 2  
A U CI N F _ pr e d                         h* n g/ m L             6 7 6. 7 6 8 9  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g               1. 5 0 3 9  
A U C _ % E xtr a p _ pr e d                          %               6. 7 1 8 7  
V z _ F _ pr e d                                 L           3 5 0 7 7. 0 0 0 9  
Cl _ F _ pr e d                               L/ h             6 6 4. 9 2 4 2  
A U M Cl a st                          h* h* n g/ m L           3 9 0 2 9. 9 2 1 8  
A U M CI N F _ o b s                       h* h* n g/ m L           4 8 9 1 6. 9 4 0 6  
A U M C _ % E xtr a p _ o b s                          %              2 0. 2 1 1 9  
A U M CI N F _ pr e d                      h* h* n g/ m L           4 9 0 6 7. 5 5 6 5  
A U M C _ % E xtr a p _ pr e d                         %              2 0. 4 5 6 8  
M R Tl a st                                   h              6 1. 8 2 4 8  
M R TI N F _ o b s                                h              7 2. 3 5 3 1  
M R TI N F _ pr e d                               h              7 2. 5 0 2 7  
A U C 0 _ 2 4                             h* n g/ m L             1 1 7. 9 9 2 1  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 5  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 8 1 6 7       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 1 7       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0       0. 1 2 9 0                          0. 0 3 1 1 7    0. 0 4 6 7 6  
      2. 0 0 0       0. 2 9 2 0                           0. 1 3 6 4     0. 2 4 1 1  
      3. 0 0 0       0. 9 4 0 0                           0. 7 5 2 4      1. 9 4 3  
      4. 0 0 0        1. 3 7 0                            1. 9 0 7      6. 0 9 3  
      6. 0 0 0        2. 1 7 0                            5. 4 4 7      2 4. 5 9  
      8. 0 0 0        2. 8 6 0                            1 0. 4 8      6 0. 4 9  
      1 2. 0 0        4. 1 1 0                            2 4. 4 2      2 0 4. 9  
      1 6. 0 0        5. 6 3 0                            4 3. 9 0      4 8 3. 7  
      2 4. 0 0        8. 3 6 0                            9 9. 8 6      1 6 4 7.  
      3 6. 0 0        1 0. 0 0                            2 1 0. 0      5 0 1 0.  
      4 8. 0 0        1 1. 6 0                            3 3 9. 6 1. 0 5 1 e + 0 0 4  
      6 0. 0 0        9. 0 0 0                            4 6 2. 6 1. 7 1 2 e + 0 0 4  
      7 2. 0 0 *      9. 3 8 0      9. 7 9 7    -0. 4 1 6 7      5 7 2. 8 2. 4 4 1 e + 0 0 4      1. 0 0 0  
      9 6. 0 0 *      7. 0 5 0      6. 6 7 0     0. 3 8 0 4      7 6 8. 7 4. 0 7 5 e + 0 0 4      1. 0 0 0  
      1 2 0. 0 *      4. 7 3 0      4. 5 4 1     0. 1 8 9 4      9 0 8. 2 5. 5 7 1 e + 0 0 4      1. 0 0 0  
      1 4 4. 0 *      2. 8 7 0      3. 0 9 1    -0. 2 2 1 2      9 9 7. 5 6. 7 4 1 e + 0 0 4      1. 0 0 0  
      1 6 8. 0 *      2. 1 5 0      2. 1 0 4    0. 0 4 5 5 1      1 0 5 7. 7. 6 7 1 e + 0 0 4      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
Pa ge 1 7 4 of 3 3 1
PI
PI


 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 1 5  
R s q _ a dj u st e d                                              0. 9 8 8 7  
C orr _ X Y                                                  -0. 9 9 5 8  
N o _ p oi nt s _l a m b d a _ z                                        5  
L a m b d a _ z                                1/ h               0. 0 1 6 0  
L a m b d a _ z _l o w er                            h              7 2. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              4 3. 2 6 6 0  
Tl a g                                      h               1. 0 1 6 7  
T m a x                                      h              4 8. 0 0 0 0  
C m a x                                  n g/ m L              1 1. 6 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 0 2 5 8  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                  n g/ m L               2. 1 5 0 0  
A U Cl a st                             h* n g/ m L            1 0 5 7. 3 5 6 3  
A U C all                              h* n g/ m L            1 0 5 7. 3 5 6 3  
A U CI N F _ o b s                          h* n g/ m L            1 1 9 1. 5 5 8 6  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g               2. 6 4 7 9  
A U C _ % E xtr a p _ o b s                           %              1 1. 2 6 2 8  
V z _ F _ o b s                                  L           2 3 5 7 3. 2 1 5 9  
Cl _ F _ o b s                                L/ h             3 7 7. 6 5 6 6  
A U CI N F _ pr e d                         h* n g/ m L            1 1 8 8. 7 1 8 1  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g               2. 6 4 1 6  
A U C _ % E xtr a p _ pr e d                          %              1 1. 0 5 0 7  
V z _ F _ pr e d                                 L           2 3 6 2 9. 5 4 5 8  
Cl _ F _ pr e d                               L/ h             3 7 8. 5 5 9 1  
A U M Cl a st                          h* h* n g/ m L           7 6 7 0 8. 7 9 1 8  
A U M CI N F _ o b s                       h* h* n g/ m L          1 0 7 6 3 1. 6 6 3 8  
A U M C _ % E xtr a p _ o b s                          %              2 8. 7 3 0 3  
A U M CI N F _ pr e d                      h* h* n g/ m L          1 0 6 9 7 7. 1 4 9 5  
A U M C _ % E xtr a p _ pr e d                         %              2 8. 2 9 4 2  
M R Tl a st                                   h              7 2. 5 4 7 7  
M R TI N F _ o b s                                h              9 0. 3 2 8 5  
M R TI N F _ pr e d                               h              8 9. 9 9 3 7  
A U C 0 _ 2 4                             h* n g/ m L              9 9. 8 5 7 4  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 7 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 7: 2 6  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 6 6 7       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
Pa ge 1 7 5 of 3 3 1
PI
PI


      1.000       0.1640                          
0.02050    0.
02050 
      1.500       0.4010                           0.1618     0.2119 
      2.000       0.7880                           0.4590     0.7563 
      3.000        1.460                            1.583      3.734 
      4.000        2.380                            3.503      10.68 
      6.000        3.060                            8.943      38.56 
      8.000        3.960                            15.96      88.60 
      12.00        4.060                         
   32.00      249.4 
      16.00        5.150                            50.42      511.6 
      24.00        5.630                            93.54      1382.
 
      36.00        3.300                            145.9      2924.
 
      48.00        3.940                            
189.3      4772.
 
      60.00        2.300                            225.9      6726.
 
      72.00 *      2.500      2.432    0.06831      254.7      8634.      1.000 
      96.00 *      1.360      1.427   
-0.06720      299.6 1.235e+004      1.000
 
      120.2 *     0.8770     0.8349    0.04214      326.2 1.520e+004      1.000
 
      144.0 *     0.4610     0.4916   
-0.03063      341.6 1.722e+004      1.000
 
      168.0 *     0.2990     0.2885    0.01046      350.6 1.862e+004      1.000
 
 
 
*) Starred values were included in the estimation of Lambda_z.
 
 
 
Final Parameters
 
---------------  
Rsq                                                       0.9962  
Rsq_adjusted                                              0.9949 
Corr_XY                                                  - 0.9981
 
No_points_lambda_z                                        5
 
Lambda_z                                1/h               0.0222
 
Lambda_z_lower                            h              72.0000
 
Lambda_z_upper                            h             168.0000
 
HL_Lambda_z                               h              31.2185
 
Tlag                                      h               0.7500 
Tmax                                      h              24.0000 
Cmax    
                              ng/mL               5.6300
 
Cmax_D                             ng/mL/mg               0.0125 
Tlast                                     h             168.0000
 
Clast                                 ng/mL               0.2990 
AUCl
ast                             h*ng/mL             350.6205 
AUCall                              h*ng/mL             350.6205 
AUCINF_obs                          h*ng/mL             364.0871 
AUCINF_D_obs                     h*ng/mL/mg               0.8091 
AUC_%Extrap_obs                           %               3.6987 
Vz_F_obs                                  L           55666.5119
 
Cl_F_obs                                L/h            1235.9680
 
AUCINF_pred                         h*ng/mL             363.6161
 
AUCINF_D_pred                    h*ng/mL/mg               0.8080 
AUC_%Extrap_pred                          %               3.5740 
Vz_F_pred                                 L           55738.6113
 
Cl_F_pred                               L/h            1237.5688
 
AUMClast                          h*h*ng/mL           18616.1151 
AUMCINF_obs                       h*h*ng/mL           21485.0235 
AUMC_%Extrap_obs                          %              13.3531 
AUMCINF_pred                      h*h*ng/mL           
21384.6914 
AUMC_%Extrap_pred                         %              12.9465 
MRTlast                                   h              53.0948 
MRTINF_obs                                h              59.0107
 
MRTINF_pred                               h              58.8112
 
AUC0_24                             h*ng/mL              93.5430
 
 
 
 
Page 176 of 331


Wi n N o nli n C or e O ut p ut 
Wi n N o nli n C or e O ut p ut – – T e p oti ni b M et a b olit e M S C 2 5 7 1 1 0 9 A
T e p oti ni b M et a b olit e M S C 2 5 7 1 1 0 9 A  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 0  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                            0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0        1. 0 8 0                           0. 1 3 5 0     0. 1 3 5 0  
      1. 6 0 0        1. 8 5 0                            1. 0 1 4      1. 3 4 7  
      2. 2 1 7        4. 9 6 0                            3. 1 1 4      5. 6 5 0  
      3. 0 0 0        1 0. 2 0                            9. 0 5 1      2 1. 9 4  
      4. 0 0 0        1 6. 6 0                            2 2. 4 5      7 0. 4 4  
      6. 0 0 0        2 4. 1 0                            6 3. 1 5      2 8 1. 4  
      8. 0 0 0        3 4. 3 0                            1 2 1. 6      7 0 0. 4  
      1 2. 0 0        4 2. 0 0                            2 7 4. 2      2 2 5 7.  
      1 6. 0 0        5 2. 2 0                            4 6 2. 6      4 9 3 6.  
      2 4. 0 2        8 5. 1 0                            1 0 1 3. 1. 6 4 8 e + 0 0 4  
      3 6. 0 0        7 9. 7 0                            2 0 0 0. 4. 6 0 3 e + 0 0 4  
      4 8. 0 2        9 7. 9 0                            3 0 6 7. 9. 1 5 1 e + 0 0 4  
      6 0. 0 0        7 2. 6 0                            4 0 8 1. 1. 4 6 0 e + 0 0 5  
      7 2. 0 0        7 0. 5 0                            4 9 4 0. 2. 0 2 6 e + 0 0 5  
      9 6. 0 2 *      5 2. 4 0      5 2. 2 7     0. 1 3 2 4      6 4 0 5. 3. 2 4 8 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      3 2. 9 0      3 2. 6 6     0. 2 4 4 8      7 4 1 0. 4. 3 2 4 e + 0 0 5      1. 0 0 0  
      1 4 4. 1 *      1 9. 9 0      2 0. 3 6    -0. 4 5 5 3      8 0 3 3. 5. 1 4 1 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      1 2. 9 0      1 2. 7 4     0. 1 6 1 8      8 4 1 9. 5. 7 4 0 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 9 3  
R s q _ a dj u st e d                                              0. 9 9 9 0  
C orr _ X Y                                                  -0. 9 9 9 7  
N o _ p oi nt s _l a m b d a _ z                                        4  
L a m b d a _ z                                1/ h               0. 0 1 9 6  
L a m b d a _ z _l o w er                            h              9 6. 0 1 6 7  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 5. 3 4 2 1  
Tl a g                                      h               0. 7 5 0 0  
T m a x                                      h              4 8. 0 1 6 7  
C m a x                                  n g/ m L              9 7. 9 0 0 0  
Pa ge 1 7 7 of 3 3 1
PI
PI


C m a x _ D                             n g/ m L/ m g               0. 2 1 7 6  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a s t                                 n g/ m L              1 2. 9 0 0 0 
A U Cl a st                             h* n g/ m L            8 4 1 8. 6 3 4 6  
A U C all                              h* n g/ m L            8 4 1 8. 6 3 4 6  
A U CI N F _ o b s                          h* n g/ m L            9 0 7 6. 3 7 9 1  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              2 0. 1 6 9 7  
A U C _ % E xtr a p _ o b s                           %               7. 2 4 6 8  
V z _ F _ o b s                                  L            2 5 2 7. 9 4 3 6  
Cl _ F _ o b s                                L/ h              4 9. 5 7 9 2  
A U CI N F _ pr e d                         h* n g/ m L            9 0 6 8. 1 2 8 6  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              2 0. 1 5 1 4  
A U C _ % E xtr a p _ pr e d                          %               7. 1 6 2 4  
V z _ F _ pr e d                                 L            2 5 3 0. 2 4 3 6  
Cl _ F _ pr e d                               L/ h              4 9. 6 2 4 4  
A U M Cl a st                          h* h* n g/ m L          5 7 3 9 8 1. 3 7 5 8  
A U M CI N F _ o b s                       h* h* n g/ m L          7 1 8 0 1 9. 4 8 2 8 
A U M C _ % E xtr a p _ o b s                          %              2 0. 0 6 0 5  
A U M CI N F _ pr e d                      h* h* n g/ m L          7 1 6 2 1 2. 7 1 9 9  
A U M C _ % E xtr a p _ pr e d                         %              1 9. 8 5 8 8  
M R Tl a st                                    h              6 8 . 1 7 9 9 
M R TI N F _ o b s                                h              7 9. 1 0 8 6  
M R TI N F _ pr e d                               h              7 8. 9 8 1 3  
A U C 0 _ 2 4                             h* n g/ m L            1 0 1 1. 4 7 7 8  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E R I O D = 1, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3 
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 0  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 3 3 3       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 6 0 5 0                          0. 0 8 0 6 7    0. 0 8 0 6 7  
      1. 5 0 0        2. 3 6 0                           0. 8 2 1 9      1. 1 1 7  
      2. 0 0 0        5. 2 2 0                            2. 7 1 7      4. 6 1 2  
      3. 0 0 0        1 2. 8 0                            1 1. 7 3      2 9. 0 3  
      4. 0 0 0        2 1. 1 0                            2 8. 6 8      9 0. 4 3  
      6. 0 0 0        2 6. 9 0                            7 6. 6 8      3 3 6. 2  
      8. 0 5 0        3 7. 0 0                            1 4 2. 2      8 0 7. 0  
      1 2. 0 0        4 7. 7 0                            3 0 9. 5      2 5 2 6.  
      1 6. 0 5        6 0. 3 0                            5 2 8. 2      5 6 4 5.  
      2 4. 0 2        8 6. 2 0                            1 1 1 2. 1. 7 7 5 e + 0 0 4  
      3 6. 0 0        8 5. 0 0                            2 1 3 7. 4. 8 5 1 e + 0 0 4  
      4 8. 0 0        9 1. 0 0                            3 1 9 3. 9. 3 0 8 e + 0 0 4  
      6 0. 0 0        5 8. 8 0                            4 0 7 8. 1. 4 0 5 e + 0 0 5  
      7 2. 0 0 *      6 3. 1 0      5 6. 5 8      6. 5 1 6      4 8 1 0. 1. 8 8 9 e + 0 0 5      1. 0 0 0  
Pa ge 1 7 8 of 3 3 1
PI
PI


      9 5. 7 3 *      2 6. 9 0      2 7. 7 7    -0. 8 6 7 2      5 8 1 7. 2. 7 1 7 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      1 2. 0 0      1 3. 4 1     -1. 4 1 0      6 2 6 5. 3. 1 9 3 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      5. 8 0 0      6. 5 2 8    -0. 7 2 8 1      6 4 7 0. 3. 4 6 0 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      3. 7 0 0      3. 1 7 8     0. 5 2 2 0      6 5 8 2. 3. 6 3 4 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 8 8 1  
R s q _ a dj u st e d                                              0. 9 8 4 2  
C orr _ X Y                                                  -0. 9 9 4 1  
N o _ p oi nt s _l a m b d a _ z                                        5  
L a m b d a _ z                                1/ h               0. 0 3 0 0  
L a m b d a _ z _l o w er                            h              7 2. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              2 3. 1 0 9 1  
Tl a g                                      h               0. 7 3 3 3  
T m a x                                      h              4 8. 0 0 0 0  
C m a x                                  n g/ m L              9 1. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 2 0 2 2  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L               3. 7 0 0 0  
A U Cl a st                             h* n g/ m L            6 5 8 2. 0 4 4 7  
A U C all                              h* n g/ m L            6 5 8 2. 0 4 4 7  
A U CI N F _ o b s                          h* n g/ m L            6 7 0 5. 4 0 0 4  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              1 4. 9 0 0 9  
A U C _ % E xtr a p _ o b s                           %               1. 8 3 9 6  
V z _ F _ o b s                                  L            2 2 3 7. 4 0 9 0  
Cl _ F _ o b s                                L/ h              6 7. 1 1 0 1  
A U CI N F _ pr e d                         h* n g/ m L            6 6 8 7. 9 9 7 1  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              1 4. 8 6 2 2  
A U C _ % E xtr a p _ pr e d                          %               1. 5 8 4 2  
V z _ F _ pr e d                                 L            2 2 4 3. 2 3 1 1  
Cl _ F _ pr e d                               L/ h              6 7. 2 8 4 7  
A U M Cl a st                          h* h* n g/ m L          3 6 3 4 3 6. 8 2 7 2  
A U M CI N F _ o b s                       h* h* n g/ m L          3 8 8 2 7 3. 1 9 2 6  
A U M C _ % E xtr a p _ o b s                          %               6. 3 9 6 6  
A U M CI N F _ pr e d                      h* h* n g/ m L          3 8 4 7 6 9. 2 1 8 9  
A U M C _ % E xtr a p _ pr e d                         %               5. 5 4 4 2  
M R Tl a st                                   h              5 5. 2 1 6 4  
M R TI N F _ o b s                                h              5 7. 9 0 4 5  
M R TI N F _ pr e d                               h              5 7. 5 3 1 3  
A U C 0 _ 2 4                             h* n g/ m L            1 1 1 0. 2 7 9 0  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 1  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
Pa ge 1 7 9 of 3 3 1
PI
PI


------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 6 8 4 0                          0. 0 8 5 5 0    0. 0 6 4 1 3  
      1. 0 0 0        1. 6 2 0                           0. 3 7 3 5     0. 3 3 0 8  
      1. 5 0 0        4. 9 4 0                            2. 0 1 4      2. 5 8 8  
      2. 0 0 0        8. 6 1 0                            5. 4 0 1      8. 7 4 6  
      3. 0 0 0        1 6. 0 0                            1 7. 7 1      4 1. 3 6  
      4. 0 0 0        2 1. 3 0                            3 6. 3 6      1 0 8. 0 
      6. 0 3 3        2 7. 1 0                            8 5. 5 6      3 6 0. 8  
      8. 0 0 0        4 3. 0 0                            1 5 4. 5      8 5 9. 8  
      1 2. 0 0        5 2. 8 0                            3 4 6. 1      2 8 1 5.  
      1 6. 0 3        7 3. 2 0                            6 0 0. 2      6 4 6 0.  
      2 4. 0 0        1 0 6. 0                            1 3 1 4. 2. 1 2 7 e + 0 0 4  
      3 6. 0 0        1 0 1. 0                            2 5 5 6. 5. 8 4 6 e + 0 0 4  
      4 8. 0 0        1 3 2. 0                            3 9 5 4. 1. 1 8 3 e + 0 0 5  
      6 0. 0 0        8 4. 0 0                            5 2 2 8. 1. 8 6 5 e + 0 0 5  
      7 2. 0 0        9 2. 5 0                            6 2 8 7. 2. 5 6 7 e + 0 0 5  
      9 6. 0 0        5 0. 3 0                            7 9 5 0. 3. 9 4 4 e + 0 0 5  
      1 2 0. 0 *      1 9. 0 0      1 8. 8 1     0. 1 9 4 4      8 7 2 1. 4. 7 6 2 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      9. 7 6 0      9. 9 6 3    -0. 2 0 3 0      9 0 5 4. 5. 1 9 7 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      5. 3 4 0      5. 2 8 5    0. 0 5 4 7 4      9 2 3 0. 5. 4 6 9 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 9 2  
R s q _ a dj u st e d                                              0. 9 9 8 4  
C orr _ X Y                                                  -0. 9 9 9 6  
N o _ p oi nt s _l a m b d a _ z                                        3  
L a m b d a _ z                                1/ h               0. 0 2 6 4  
L a m b d a _ z _l o w er                            h             1 1 9. 9 8 3 3  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              2 6. 2 2 2 6  
Tl a g                                      h               0. 5 0 0 0  
T m a x                                      h              4 8. 0 0 0 0  
C m a x                                  n g/ m L             1 3 2. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 2 9 3 3  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L               5. 3 4 0 0  
A U Cl a st                             h* n g/ m L            9 2 2 9. 8 4 4 1  
A U C all                              h* n g/ m L            9 2 2 9. 8 4 4 1  
A U CI N F _ o b s                          h* n g/ m L            9 4 3 1. 8 6 2 7  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              2 0. 9 5 9 7  
A U C _ % E xtr a p _ o b s                           %               2. 1 4 1 9  
V z _ F _ o b s                                  L            1 8 0 4. 9 4 9 7  
Cl _ F _ o b s                                L/ h              4 7. 7 1 0 6  
A U CI N F _ pr e d                         h* n g/ m L            9 4 2 9. 7 9 1 8  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              2 0. 9 5 5 1  
A U C _ % E xtr a p _ pr e d                          %               2. 1 2 0 4  
V z _ F _ pr e d                                 L            1 8 0 5. 3 4 6 0  
Cl _ F _ pr e d                               L/ h              4 7. 7 2 1 1  
A U M Cl a st                          h* h* n g/ m L          5 4 6 9 3 7. 6 9 6 7  
A U M CI N F _ o b s                       h* h* n g/ m L          5 8 8 5 1 9. 4 2 1 5  
A U M C _ % E xtr a p _ o b s                          %               7. 0 6 5 5  
A U M CI N F _ pr e d                      h* h* n g/ m L          5 8 8 0 9 3. 1 7 3 7  
A U M C _ % E xtr a p _ pr e d                         %               6. 9 9 8 1  
M R Tl a st                                   h              5 9. 2 5 7 5  
M R TI N F _ o b s                                h              6 2. 3 9 6 9  
M R TI N F _ pr e d                               h              6 2. 3 6 5 4  
A U C 0 _ 2 4                             h* n g/ m L            1 3 1 4. 0 0 7 7  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
Pa ge 1 8 0 of 3 3 1
PI


 
                                                  Date:    
 
                                                  Time:     09:24:10 
 
 
                  WINNONLIN NONCOMPARTMENTAL ANALYSIS PROGRAM 
                                   7.0.0.2535 
                            Core Version 04Jun2007 
 
Settings 
-------- 
Model:  Plasma Data, Extravascular Administration 
Number of nonmissing observations:   22 
Dose time:      0.00 
Dose amount:      450.00 
Calculation method:  Linear Trapezoidal Rule for for Increasing Values, 
                     Log Trapezoidal Rule for Decreasing Values 
Weighting for lambda_z calculations:  Uniform weighting 
Lambda_z method:  Find best fit for lambda_z,  Log regression 
 
 
Summary Table 
------------- 
      Time         Conc.      Pred.    Residual      AUC       AUMC      Weight 
          h       ng/mL       ng/mL       ng/mL     h*ng/mL   h*h*ng/mL 
------------------------------------------------------------------------------- 
     0.0000       0.0000                           0.0000     0.0000 
     0.2500       0.0000                           0.0000     0.0000 
     0.5000       0.0000                           0.0000     0.0000 
     0.7500       0.0000                           0.0000     0.0000 
      1.000       0.7680                          0.09600    0.09600 
      1.500        1.120                           0.5680     0.7080 
      2.000        1.680                            1.268      1.968 
      3.000        5.380                            4.798      11.72 
      4.000        10.20                            12.59      40.19 
      6.000        21.30                            44.09      208.8 
      8.067        35.20                            102.5      634.3 
      12.00        44.20                            258.6      2236. 
      16.00        56.90                            460.8      5117. 
      24.02        90.50                            1052. 1.748e+004 
      36.00        81.20                            2079. 4.821e+004 
      48.00        110.0                            3227. 9.743e+004 
      60.00        68.60                            4279. 1.537e+005 
      72.00 *      68.10      71.76     -3.665      5099. 2.079e+005      1.000 
      96.07 *      47.50      43.06      4.437      6475. 3.225e+005      1.000 
      120.0 *      24.20      25.90     -1.705      7303. 4.108e+005      1.000 
      144.0 *      16.40      15.57     0.8281      7783. 4.739e+005      1.000 
      168.0 *      9.080      9.351    -0.2708      8081. 5.200e+005      1.000 
 
 
*) Starred values were included in the estimation of Lambda_z. 
 
 
Final Parameters 
--------------- 
Rsq                                                       0.9921 
Rsq_adjusted                                              0.9895 
Corr_XY                                                  -0.9961 
No_points_lambda_z                                        5 
Lambda_z                                1/h               0.0212 
Lambda_z_lower                            h              72.0000 
Lambda_z_upper                            h             168.0333 
HL_Lambda_z                               h              32.6631 
Tlag                                      h               0.7500 
Tmax                                      h              48.0000 
Cmax                                  ng/mL             110.0000 
Cmax_D                             ng/mL/mg               0.2444 
Tlast                                     h             168.0333 
Clast                                 ng/mL               9.0800 
AUClast                             h*ng/mL            8080.9986 
AUCall                              h*ng/mL            8080.9986 
AUCINF_obs                          h*ng/mL            8508.8741 
AUCINF_D_obs                     h*ng/mL/mg              18.9086 
Page 181 of 331
PI


A U C _ % E xtr a p _ o b s                           %               5. 0 2 8 6  
V z _ F _ o b s                                  L            2 4 9 2. 1 3 7 5  
Cl _ F _ o b s                                L/ h              5 2. 8 8 6 0  
A U CI N F _ pr e d                         h* n g/ m L            8 5 2 1. 6 3 2 7  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              1 8. 9 3 7 0  
A U C _ % E xtr a p _ pr e d                          %               5. 1 7 0 8  
V z _ F _ pr e d                                 L            2 4 8 8. 4 0 6 3  
Cl _ F _ pr e d                               L/ h              5 2. 8 0 6 8  
A U M Cl a st                          h* h* n g/ m L          5 2 0 0 0 0. 0 0 3 1  
A U M CI N F _ o b s                       h* h* n g/ m L          6 1 2 0 6 0. 0 6 7 8  
A U M C _ % E xtr a p _ o b s                          %              1 5. 0 4 1 0  
A U M CI N F _ pr e d                      h* h* n g/ m L          6 1 4 8 0 5. 1 6 2 5  
A U M C _ % E xtr a p _ pr e d                         %              1 5. 4 2 0 4  
M R Tl a st                                   h              6 4. 3 4 8 5  
M R TI N F _ o b s                                h              7 1. 9 3 2 0  
M R TI N F _ pr e d                               h              7 2. 1 4 6 4  
A U C 0 _ 2 4                             h* n g/ m L            1 0 5 0. 1 4 5 2  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 0  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 3 3       0. 8 5 7 0                           0. 1 2 1 4     0. 1 2 5 5  
      1. 5 0 0        2. 3 5 0                           0. 8 6 9 7      1. 1 5 5  
      2. 0 1 7        4. 4 0 0                            2. 6 1 3      4. 3 5 7  
      3. 0 0 0        1 3. 9 0                            1 1. 6 1      2 9. 2 2  
      4. 0 0 0        2 0. 7 0                            2 8. 9 1      9 1. 4 7  
      6. 0 0 0        2 9. 5 0                            7 9. 1 1      3 5 1. 3  
      8. 0 0 0        3 9. 5 0                            1 4 8. 1      8 4 4. 3  
      1 2. 0 0        6 1. 7 0                            3 5 0. 5      2 9 5 7.  
      1 6. 0 0        7 7. 3 0                            6 2 8. 5      6 9 1 1.  
      2 4. 0 3        1 1 3. 0                            1 3 9 3. 2. 2 7 9 e + 0 0 4  
      3 6. 0 0        1 2 7. 0                            2 8 2 9. 6. 6 3 9 e + 0 0 4  
      4 8. 0 0        1 3 3. 0                            4 3 8 9. 1. 3 2 1 e + 0 0 5  
      6 0. 0 0        9 9. 3 0                            5 7 7 3. 2. 0 6 5 e + 0 0 5  
      7 2. 0 0        9 4. 7 0                            6 9 3 7. 2. 8 3 2 e + 0 0 5  
      9 6. 0 0 *      7 7. 0 0      7 3. 8 4      3. 1 5 5      8 9 9 0. 4. 5 4 8 e + 0 0 5      1. 0 0 0  
      1 2 0. 3 *      3 9. 9 0      4 4. 3 0     -4. 4 0 5 1. 0 3 6 e + 0 0 4 6. 0 1 1 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      2 9. 2 0      2 6. 8 8      2. 3 1 8 1. 1 1 7 e + 0 0 4 7. 0 8 1 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      1 5. 9 0      1 6. 2 2    -0. 3 1 8 9 1. 1 7 0 e + 0 0 4 7. 8 9 4 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
Pa ge 1 8 2 of 3 3 1
PI
PI


 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 8 4 6  
R s q _ a dj u st e d                                              0. 9 7 6 9  
C orr _ X Y                                                  -0. 9 9 2 3  
N o _ p oi nt s _l a m b d a _ z                                        4 
L a m b d a _ z                                1/ h               0. 0 2 1 1  
L a m b d a _ z _l o w er                            h              9 6. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 2. 9 2 4 6  
Tl a g                                      h               0. 7 5 0 0  
T m a x                                      h              4 8. 0 0 0 0  
C m a x                                  n g/ m L             1 3 3. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 2 9 5 6  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L              1 5. 9 0 0 0  
A U Cl a st                             h* n g/ m L           1 1 6 9 7. 6 4 7 2  
A U C all                              h* n g/ m L           1 1 6 9 7. 6 4 7 2  
A U CI N F _ o b s                          h* n g/ m L           1 2 4 5 2. 9 0 0 8  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              2 7. 6 7 3 1  
A U C _ % E xtr a p _ o b s                           %               6. 0 6 4 9  
V z _ F _ o b s                                  L            1 7 1 6. 4 7 5 7  
Cl _ F _ o b s                                L/ h              3 6. 1 3 6 2  
A U CI N F _ pr e d                         h* n g/ m L           1 2 4 6 8. 0 5 0 6  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              2 7. 7 0 6 8  
A U C _ % E xtr a p _ pr e d                          %               6. 1 7 9 0  
V z _ F _ pr e d                                 L            1 7 1 4. 3 9 0 1  
Cl _ F _ pr e d                               L/ h              3 6. 0 9 2 3  
A U M Cl a st                          h* h* n g/ m L          7 8 9 3 5 5. 4 2 6 9  
A U M CI N F _ o b s                       h* h* n g/ m L          9 5 2 1 1 2. 7 4 9 7  
A U M C _ % E xtr a p _ o b s                          %              1 7. 0 9 4 3  
A U M CI N F _ pr e d                      h* h* n g/ m L          9 5 5 3 7 7. 5 3 1 1  
A U M C _ % E xtr a p _ pr e d                         %              1 7. 3 7 7 6  
M R Tl a st                                   h              6 7. 4 7 9 8  
M R TI N F _ o b s                                h              7 6. 4 5 7 1  
M R TI N F _ pr e d                               h              7 6. 6 2 6 1  
A U C 0 _ 2 4                             h* n g/ m L            1 3 8 9. 1 1 8 4  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 3  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m  w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
Pa ge 1 8 3 of 3 3 1
PI
PI


     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 5 6 6 0                          0. 0 7 0 7 5    0. 0 7 0 7 5  
      1. 5 0 0       0. 9 8 1 0                           0. 4 5 7 5     0. 5 8 0 1  
      2. 0 0 0        2. 0 4 0                            1. 2 1 3      1. 9 6 8  
      3. 0 0 0        4. 7 8 0                            4. 6 2 3      1 1. 1 8  
      4. 0 0 0        1 1. 1 0                            1 2. 5 6      4 0. 5 5  
      6. 0 0 0        1 6. 5 0                            4 0. 1 6      1 8 3. 9  
      8. 0 0 0        2 8. 7 0                            8 5. 3 6      5 1 2. 5  
      1 2. 0 0        5 3. 0 0                            2 4 8. 8      2 2 4 4.  
      1 6. 0 0        7 8. 3 0                            5 1 1. 4      6 0 2 1.  
      2 4. 0 0        1 1 9. 0                            1 3 0 1. 2. 2 4 6 e + 0 0 4  
      3 6. 0 0        9 3. 3 0                            2 5 6 8. 6. 0 1 8 e + 0 0 4  
      4 8. 0 0        1 1 0. 0                            3 7 8 8. 1. 1 2 0 e + 0 0 5  
      6 0. 0 0        7 5. 0 0                             4 8 8 5. 1. 7 0 8 e + 0 0 5  
      7 2. 0 0        6 9. 8 0                            5 7 5 3. 2. 2 8 1 e + 0 0 5  
      9 6. 0 0 *      6 4. 3 0      6 3. 9 9     0. 3 0 9 8      7 3 6 1. 3. 6 2 9 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      3 2. 7 0      3 5. 3 9     -2. 6 9 2      8 4 8 3. 4. 8 2 5 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      2 2. 6 0      1 9. 5 7      3. 0 2 5      9 1 3 9. 5. 6 8 6 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      1 0. 1 0      1 0. 8 3    -0. 7 2 6 3      9 5 1 1. 6. 2 6 2 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P a r a m et er s 
--------------- 
R s q                                                       0. 9 8 2 2  
R s q _ a dj u st e d                                              0. 9 7 3 3  
C orr _ X Y                                                  -0. 9 9 1 1  
N o _ p oi nt s _l a m b d a _ z                                        4 
L a m b d a _ z                                1/ h               0. 0 2 4 7  
L a m b d a _ z _l o w er                            h              9 6. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              2 8. 0 8 8 7  
Tl a g                                      h               0. 7 5 0 0  
T m a x                                      h              2 4. 0 0 0 0  
C m a x                                  n g/ m L             1 1 9. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 2 6 4 4  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L              1 0. 1 0 0 0  
A U Cl a st                             h* n g/ m L            9 5 1 1. 4 8 8 5  
A U C all                              h* n g/ m L            9 5 1 1. 4 8 8 5  
A U CI N F _ o b s                          h* n g/ m L            9 9 2 0. 7 7 5 2  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              2 2. 0 4 6 2  
A U C _ % E xtr a p _ o b s                           %               4. 1 2 5 6  
V z _ F _ o b s                                  L            1 8 3 8. 1 1 7 4  
Cl _ F _ o b s                                L/ h              4 5. 3 5 9 4  
A U CI N F _ pr e d                         h* n g/ m L            9 9 5 0. 2 0 8 3  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              2 2. 1 1 1 6  
A U C _ % E xtr a p _ pr e d                          %               4. 4 0 9 2  
V z _ F _ pr e d                                 L            1 8 3 2. 6 8 0 2  
Cl _ F _ pr e d                               L/ h              4 5. 2 2 5 2  
A U M Cl a st                          h* h* n g/ m L          6 2 6 1 6 1. 4 0 4 3  
A U M CI N F _ o b s                       h* h* n g/ m L          7 1 1 5 0 7. 2 9 0 9  
A U M C _ % E xtr a p _ o b s                          %              1 1. 9 9 5 1  
A U M CI N F _ pr e d                      h* h* n g/ m L          7 1 7 6 4 4. 7 7 0 9  
A U M C _ % E xtr a p _ pr e d                         %              1 2. 7 4 7 7  
M R Tl a st                                   h              6 5. 8 3 2 1  
M R TI N F _ o b s                                h              7 1. 7 1 8 9  
M R TI N F _ pr e d                               h              7 2. 1 2 3 6  
A U C 0 _ 2 4                             h* n g/ m L            1 3 0 0. 5 6 2 8  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 2  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
Pa ge 1 8 4 of 3 3 1
PI
PI


                            Core Version 04Jun2007 
 
Settings 
-------- 
Model:  Plasma Data, Extravascular Administration 
Number of nonmissing observations:   22 
Dose time:      0.00 
Dose amount:      450.00 
Calculation method:  Linear Trapezoidal Rule for for Increasing Values, 
                     Log Trapezoidal Rule for Decreasing Values 
Weighting for lambda_z calculations:  Uniform weighting 
Lambda_z method:  Find best fit for lambda_z,  Log regression 
 
 
Summary Table 
------------- 
      Time         Conc.      Pred.    Residual      AUC       AUMC      Weight 
          h       ng/mL       ng/mL       ng/mL     h*ng/mL   h*h*ng/mL 
------------------------------------------------------------------------------- 
     0.0000       0.7400                           0.0000     0.0000 
     0.2500       0.6110                           0.1684    0.02037 
     0.5000       0.6370                           0.3244    0.07928 
     0.7500       0.8280                           0.5075     0.1967 
      1.000        1.160                           0.7560     0.4193 
      1.500        2.320                            1.626      1.579 
      2.000        3.860                            3.171      4.379 
      3.000        6.730                            8.466      18.33 
      4.000        13.30                            18.48      55.03 
      6.000        25.10                            56.88      258.8 
      8.000        36.00                            118.0      697.4 
      12.00        57.90                            305.8      2663. 
      16.00        74.00                            569.6      6421. 
      24.00        122.0                            1354. 2.287e+004 
      36.00        126.0                            2842. 6.765e+004 
      48.00        173.0                            4636. 1.447e+005 
      60.00        139.0                            6500. 2.450e+005 
      72.00        153.0                            8252. 3.611e+005 
      96.00 *      144.0      146.7     -2.673 1.182e+004 6.600e+005      1.000 
      120.0 *      97.70      100.6     -2.903 1.468e+004 9.671e+005      1.000 
      144.0 *      77.30      68.98      8.315 1.677e+004 1.242e+006      1.000 
      168.0 *      44.30      47.33     -3.029 1.819e+004 1.463e+006      1.000 
 
 
*) Starred values were included in the estimation of Lambda_z. 
 
 
Final Parameters 
--------------- 
Rsq                                                       0.9746 
Rsq_adjusted                                              0.9619 
Corr_XY                                                  -0.9872 
No_points_lambda_z                                        4 
Lambda_z                                1/h               0.0157 
Lambda_z_lower                            h              96.0000 
Lambda_z_upper                            h             168.0000 
HL_Lambda_z                               h              44.1229 
Tlag                                      h               0.0000 
Tmax                                      h              48.0000 
Cmax                                  ng/mL             173.0000 
Cmax_D                             ng/mL/mg               0.3844 
Tlast                                     h             168.0000 
Clast                                 ng/mL              44.3000 
AUClast                             h*ng/mL           18193.1875 
AUCall                              h*ng/mL           18193.1875 
AUCINF_obs                          h*ng/mL           21013.1420 
AUCINF_D_obs                     h*ng/mL/mg              46.6959 
AUC_%Extrap_obs                           %              13.4200 
Vz_F_obs                                  L            1363.2010 
Cl_F_obs                                L/h              21.4152 
AUCINF_pred                         h*ng/mL           21205.9543 
AUCINF_D_pred                    h*ng/mL/mg              47.1243 
AUC_%Extrap_pred                          %              14.2072 
Vz_F_pred                                 L            1350.8063 
Page 185 of 331


Cl _ F _ pr e d                               L/ h              2 1. 2 2 0 5  
A U M Cl a st                           h* h* n g/ m L         1 4 6 2 5 0 2. 4 5 8 5  
A U M CI N F _ o b s                       h* h* n g/ m L         2 1 1 5 7 6 1. 4 4 0 5  
A U M C _ % E xtr a p _ o b s                          %              3 0. 8 7 5 8  
A U M CI N F _ pr e d                      h* h* n g/ m L         2 1 6 0 4 2 7. 5 4 3 2  
A U M C _ % E xtr a p _ pr e d                         %              3 2. 3 0 5 0  
M R Tl a st                                   h              8 0. 3 8 7 4  
M R TI N F _ o b s                                h             1 0 0. 6 8 7 5  
M R TI N F _ pr e d                               h             1 0 1. 8 7 8 3  
A U C 0 _ 2 4                             h* n g/ m L            1 3 5 3. 5 8 1 0  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 1  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 3 3 3       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0        1. 1 6 0                           0. 2 9 0 0     0. 4 3 5 0  
      2. 0 0 0        1. 8 8 0                            1. 0 5 0      1. 8 1 0  
      3. 0 0 0        5. 6 3 0                            4. 8 0 5      1 2. 1 4  
      4. 0 0 0        1 0. 6 0                            1 2. 9 2      4 1. 7 8  
      6. 0 0 0        1 6. 9 0                            4 0. 4 2      1 8 5. 6  
      8. 0 0 0        2 7. 9 0                            8 5. 2 2      5 1 0. 2  
      1 2. 0 0        4 8. 9 0                            2 3 8. 8      2 1 3 0.  
      1 6. 0 0        6 6. 0 0                            4 6 8. 6      5 4 1 6.  
      2 4. 0 2        9 1. 5 0                            1 1 0 0. 1. 8 4 6 e + 0 0 4  
      3 6. 0 0        1 0 2. 0                            2 2 5 9. 5. 3 6 3 e + 0 0 4  
      4 8. 0 0        1 1 2. 0                            3 5 4 3. 1. 0 7 9 e + 0 0 5  
      6 0. 0 2        9 2. 0 0                            4 7 6 5. 1. 7 3 7 e + 0 0 5  
      7 2. 0 0 *      7 7. 4 0      7 7. 1 3     0. 2 6 8 8      5 7 7 8. 2. 4 0 3 e + 0 0 5      1. 0 0 0  
      9 6. 0 0 *      4 8. 9 0      4 9. 4 9    -0. 5 9 3 8      7 2 6 7. 3. 6 4 1 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      3 2. 5 0      3 1. 7 6     0. 7 4 0 6      8 2 3 1. 4. 6 7 3 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      1 9. 9 0      2 0. 3 8    -0. 4 7 9 5      8 8 4 7. 5. 4 8 1 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      1 3. 2 0      1 3. 0 8     0. 1 2 2 8      9 2 3 9. 6. 0 8 9 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 9 3  
R s q _ a dj u st e d                                              0. 9 9 9 1  
C orr _ X Y                                                  - 0. 9 9 9 7  
Pa ge 1 8 6 of 3 3 1
PI
PI


N o _ p oi nt s _l a m b d a _ z                                        5  
L a m b d a _ z                                1/ h               0. 0 1 8 5  
L a m b d a _ z _l o w er                            h              7 2. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 7. 4 9 6 1  
Tl a g                                      h               1. 0 0 0 0  
T m a x                                      h              4 8. 0 0 0 0  
C m a x                                  n g/ m L             1 1 2. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 2 4 8 9  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L              1 3. 2 0 0 0  
A U Cl a st                             h* n g/ m L            9 2 3 8. 7 0 9 6  
A U C all                              h* n g/ m L            9 2 3 8. 7 0 9 6  
A U CI N F _ o b s                          h* n g/ m L            9 9 5 2. 7 7 0 3  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              2 2. 1 1 7 3  
A U C _ % E xtr a p _ o b s                           %               7. 1 7 4 5  
V z _ F _ o b s                                  L            2 4 4 5. 8 4 9 5  
Cl _ F _ o b s                                L/ h              4 5. 2 1 3 5  
A U CI N F _ pr e d                         h* n g/ m L            9 9 4 6. 1 2 6 2  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              2 2. 1 0 2 5  
A U C _ % E xtr a p _ pr e d                          %               7. 1 1 2 5  
V z _ F _ pr e d                                 L            2 4 4 7. 4 8 3 4  
Cl _ F _ pr e d                               L/ h              4 5. 2 4 3 7  
A U M Cl a st                          h* h* n g/ m L          6 0 8 8 9 8. 1 3 8 7  
A U M CI N F _ o b s                       h* h* n g/ m L          7 6 7 4 8 7. 8 1 4 6  
A U M C _ % E xtr a p _ o b s                          %              2 0. 6 6 3 5  
A U M CI N F _ pr e d                      h* h* n g/ m L          7 6 6 0 1 2. 1 9 8 0  
A U M C _ % E xtr a p _ pr e d                         %              2 0. 5 1 0 6  
M R Tl a st                                   h              6 5. 9 0 7 3  
M R TI N F _ o b s                                h              7 7. 1 1 3 0  
M R TI N F _ pr e d                               h              7 7. 0 1 6 1  
A U C 0 _ 2 4                             h* n g/ m L            1 0 9 8. 4 0 7 9  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 1  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:   Pl a s m a D at a,  E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 3 3       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0       0. 6 9 3 0                           0. 1 6 1 7     0. 2 4 2 6  
      2. 0 0 0        2. 3 7 0                           0. 9 2 7 5      1. 6 8 7  
      3. 0 0 0        7. 1 7 0                            5. 6 9 7      1 4. 8 1  
      4. 0 0 0        1 3. 0 0                            1 5. 7 8      5 1. 5 7  
      6. 0 0 0        2 1. 9 0                            5 0. 6 8      2 3 5. 0  
Pa ge 1 8 7 of 3 3 1
PI
PI


      8. 0 0 0        3 1. 0 0                            1 0 3. 6      6 1 4. 4  
      1 2. 0 0        4 7. 2 0                            2 6 0. 0      2 2 4 3.  
      1 6. 0 0        6 6. 5 0                            4 8 7. 4      5 5 0 4.  
      2 4. 0 0        7 8. 6 0                            1 0 6 8. 1. 7 3 1 e + 0 0 4  
      3 6. 0 0        8 5. 3 0                            2 0 5 1. 4. 7 0 5 e + 0 0 4  
      4 8. 0 0        9 7. 5 0                            3 1 4 8. 9. 3 5 5 e + 0 0 4  
      6 0. 0 0        7 7. 7 0                            4 1 9 5. 1. 4 9 8 e + 0 0 5  
      7 2. 0 0        6 9. 2 0                            5 0 7 5. 2. 0 7 8 e + 0 0 5  
      9 6. 0 0 *      4 8. 9 0      4 8. 7 6     0. 1 3 5 6      6 4 7 8. 3. 2 4 7 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      2 8. 3 0      2 8. 0 4     0. 2 5 8 7      7 3 8 2. 4. 2 1 4 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      1 5. 7 0      1 6. 1 2    -0. 4 2 4 8      7 8 9 5. 4. 8 8 5 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      9. 4 1 0      9. 2 7 2     0. 1 3 7 7      8 1 9 0. 5. 3 4 2 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 9 3  
R s q _ a dj u st e d                                              0. 9 9 9 0  
C orr _ X Y                                                  -0. 9 9 9 7  
N o _ p oi nt s _l a m b d a _ z                                        4 
L a m b d a _ z                                1/ h               0. 0 2 3 1  
L a m b d a _ z _l o w er                            h              9 6. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 0. 0 6 4 9  
Tl a g                                      h               1. 0 3 3 3  
T m a x                                      h              4 8. 0 0 0 0  
C m a x                                  n g/ m L              9 7. 5 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 2 1 6 7  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L               9. 4 1 0 0  
A U Cl a st                             h* n g/ m L            8 1 9 0. 3 6 2 5  
A U C all                              h* n g/ m L            8 1 9 0. 3 6 2 5  
A U CI N F _ o b s                          h* n g/ m L            8 5 9 8. 5 1 5 9  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              1 9. 1 0 7 8  
A U C _ % E xtr a p _ o b s                           %               4. 7 4 6 8  
V z _ F _ o b s                                  L            2 2 6 9. 9 8 3 8  
Cl _ F _ o b s                                L/ h              5 2. 3 3 4 6  
A U CI N F _ pr e d                         h* n g/ m L            8 5 9 2. 5 4 5 1  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              1 9. 0 9 4 5  
A U C _ % E xtr a p _ p r e d                          %               4. 6 8 0 6 
V z _ F _ pr e d                                 L            2 2 7 1. 5 6 1 2  
Cl _ F _ pr e d                               L/ h              5 2. 3 7 1 0  
A U M Cl a st                          h* h* n g/ m L          5 3 4 2 3 1. 3 5 6 4  
A U M CI N F _ o b s                       h* h* n g/ m L          6 2 0 5 0 4. 5 3 6 5  
A U M C _ % E xtr a p _ o b s                          %              1 3. 9 0 3 7  
A U M CI N F _ pr e d                      h* h* n g/ m L          6 1 9 2 4 2. 4 5 9 6  
A U M C _ % E xtr a p _ pr e d                         %              1 3. 7 2 8 2  
M R Tl a st                                   h              6 5. 2 2 6 8  
M R TI N F _ o b s                                h              7 2. 1 6 4 1  
M R TI N F _ pr e d                               h              7 2. 0 6 7 4  
A U C 0 _ 2 4                             h* n g/ m L            1 0 6 7. 7 8 2 5  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 2  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e t i m e:      0. 0 0 
Pa ge 1 8 8 of 3 3 1
PI
PI


Dose amount:      450.00 
Calculation method:  Linear Trapezoidal Rule for for Increasing Values, 
                     Log Trapezoidal Rule for Decreasing Values 
Weighting for lambda_z calculations:  Uniform weighting 
Lambda_z method:  Find best fit for lambda_z,  Log regression 
 
 
Summary Table 
------------- 
      Time         Conc.      Pred.    Residual      AUC       AUMC      Weight 
          h       ng/mL       ng/mL       ng/mL     h*ng/mL   h*h*ng/mL 
------------------------------------------------------------------------------- 
     0.0000       0.0000                           0.0000     0.0000 
     0.2500       0.0000                           0.0000     0.0000 
     0.5000       0.0000                           0.0000     0.0000 
     0.7500       0.0000                           0.0000     0.0000 
      1.000       0.5470                          0.06838    0.06838 
      1.500        1.360                           0.5451     0.7151 
      2.000        2.440                            1.495      2.445 
      3.000        5.790                            5.610      13.57 
      4.000        10.30                            13.66      42.86 
      6.000        17.60                            41.56      189.7 
      8.000        27.90                            87.06      518.5 
      12.00        44.70                            232.3      2038. 
      16.00        72.70                            467.1      5437. 
      24.00        110.0                            1198. 2.065e+004 
      36.00        119.0                            2572. 6.219e+004 
      48.00        170.0                            4306. 1.369e+005 
      60.00        153.0                            6242. 2.412e+005 
      72.00        180.0                            8240. 3.740e+005 
      96.00        155.0                       1.225e+004 7.099e+005 
      120.0 *      114.0      113.0      1.047 1.546e+004 1.054e+006      1.000 
      144.0 *      72.70      74.05     -1.353 1.766e+004 1.343e+006      1.000 
      168.0 *      49.00      48.55     0.4498 1.910e+004 1.566e+006      1.000 
 
 
*) Starred values were included in the estimation of Lambda_z. 
 
 
Final Parameters 
--------------- 
Rsq                                                       0.9986 
Rsq_adjusted                                              0.9971 
Corr_XY                                                  -0.9993 
No_points_lambda_z                                        3 
Lambda_z                                1/h               0.0176 
Lambda_z_lower                            h             120.0000 
Lambda_z_upper                            h             168.0000 
HL_Lambda_z                               h              39.4030 
Tlag                                      h               0.7500 
Tmax                                      h              72.0000 
Cmax                                  ng/mL             180.0000 
Cmax_D                             ng/mL/mg               0.4000 
Tlast                                     h             168.0000 
Clast                                 ng/mL              49.0000 
AUClast                             h*ng/mL           19100.5520 
AUCall                              h*ng/mL           19100.5520 
AUCINF_obs                          h*ng/mL           21886.0339 
AUCINF_D_obs                     h*ng/mL/mg              48.6356 
AUC_%Extrap_obs                           %              12.7272 
Vz_F_obs                                  L            1168.8256 
Cl_F_obs                                L/h              20.5611 
AUCINF_pred                         h*ng/mL           21860.4624 
AUCINF_D_pred                    h*ng/mL/mg              48.5788 
AUC_%Extrap_pred                          %              12.6251 
Vz_F_pred                                 L            1170.1928 
Cl_F_pred                               L/h              20.5851 
AUMClast                          h*h*ng/mL         1566490.8677 
AUMCINF_obs                       h*h*ng/mL         2192796.8989 
AUMC_%Extrap_obs                          %              28.5620 
AUMCINF_pred                      h*h*ng/mL         2187047.2438 
AUMC_%Extrap_pred                         %              28.3742 
MRTlast                                   h              82.0129 
Page 189 of 331


M R TI N F _ o b s                                h             1 0 0. 1 9 1 6  
M R TI N F _ pr e d                               h             1 0 0. 0 4 5 8  
A U C 0 _ 2 4                             h* n g/ m L            1 1 9 7. 8 5 5 1  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 2  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      2. 0 0 0        1. 6 5 0                           0. 4 1 2 5     0. 8 2 5 0  
      3. 0 0 0        4. 0 8 0                            3. 2 7 8      8. 5 9 5  
      4. 0 0 0        8. 4 8 0                            9. 5 5 8      3 1. 6 8  
      6. 0 0 0        1 4. 2 0                            3 2. 2 4      1 5 0. 8  
      8. 0 0 0        2 4. 2 0                            7 0. 6 4      4 2 9. 6  
      1 2. 0 0        4 7. 0 0                            2 1 3. 0      1 9 4 5.  
      1 6. 0 0        6 1. 4 0                            4 2 9. 8      5 0 3 8.  
      2 4. 0 0        1 2 9. 0                            1 1 9 1. 2. 1 3 5 e + 0 0 4  
      3 6. 0 0        1 3 1. 0                            2 7 5 1. 6. 8 2 2 e + 0 0 4  
      4 8. 0 0        1 5 6. 0                            4 4 7 3. 1. 4 1 4 e + 0 0 5  
      6 0. 0 0        1 1 0. 0                            6 0 5 3. 2. 2 6 2 e + 0 0 5  
      7 2. 0 0        1 1 6. 0                            7 4 0 9. 3. 1 5 9 e + 0 0 5  
      9 6. 0 0 *      9 0. 9 0      9 3. 6 8     -2. 7 8 1      9 8 8 0. 5. 2 2 3 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      5 8. 8 0      5 7. 5 6      1. 2 3 9 1. 1 6 5 e + 0 0 4 7. 1 1 7 e + 0 0 5      1. 0 0 0 
      1 4 4. 0 *      3 7. 1 0      3 5. 3 7      1. 7 3 3 1. 2 7 8 e + 0 0 4 8. 6 0 0 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      2 0. 9 0      2 1. 7 3    -0. 8 3 0 9 1. 3 4 6 e + 0 0 4 9. 6 4 9 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 5 7  
R s q _ a dj u st e d                                              0. 9 9 3 5  
C orr _ X Y                                                  -0. 9 9 7 8  
N o _ p oi nt s _l a m b d a _ z                                        4  
L a m b d a _ z                                1/ h               0. 0 2 0 3  
L a m b d a _ z _l o w er                            h              9 6. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 4. 1 5 5 3  
Tl a g                                      h               1. 5 0 0 0  
T m a x                                      h              4 8. 0 0 0 0  
Pa ge 1 9 0 of 3 3 1
PI
PI


C m a x                                  n g/ m L             1 5 6. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 3 4 6 7  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L              2 0. 9 0 0 0  
A U Cl a st                             h* n g/ m L           1 3 4 5 6. 8 8 3 5  
A U C all                              h* n g/ m L           1 3 4 5 6. 8 8 3 5  
A U CI N F _ o b s                          h* n g/ m L           1 4 4 8 6. 7 4 5 1  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              3 2. 1 9 2 8  
A U C _ % E xtr a p _ o b s                           %               7. 1 0 9 0  
V z _ F _ o b s                                  L            1 5 3 0. 6 4 4 3  
Cl _ F _ o b s                                L/ h              3 1. 0 6 2 9  
A U CI N F _ pr e d                         h* n g/ m L           1 4 5 2 7. 6 8 6 3  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              3 2. 2 8 3 7  
A U C _ % E xtr a p _ pr e d                          %               7. 3 7 0 8  
V z _ F _ pr e d                                 L            1 5 2 6. 3 3 0 7  
Cl _ F _ pr e d                               L/ h              3 0. 9 7 5 3  
A U M Cl a st                          h* h* n g/ m L          9 6 4 8 7 1. 5 7 2 3  
A U M CI N F _ o b s                       h* h* n g/ m L         1 1 8 8 6 3 5. 4 4 3 5  
A U M C _ % E xtr a p _ o b s                          %              1 8. 8 2 5 3  
A U M CI N F _ pr e d                      h* h* n g/ m L         1 1 9 7 5 3 0. 9 7 0 8  
A U M C _ % E xtr a p _ pr e d                         %              1 9. 4 2 8 3  
M R Tl a st                                   h              7 1. 7 0 1 0  
M R TI N F _ o b s                                h              8 2. 0 4 9 9  
M R TI N F _ pr e d                               h              8 2. 4 3 0 9  
A U C 0 _ 2 4                             h* n g/ m L            1 1 9 1. 4 3 7 5  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 0  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 6 6 7       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 1 7       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0        1. 7 0 0                           0. 4 1 0 8     0. 6 1 6 2  
      2. 0 0 0        4. 0 6 0                            1. 8 5 1      3. 2 8 4  
      3. 0 0 0        1 1. 7 0                            9. 7 3 1      2 4. 8 9  
      4. 0 0 0        2 2. 7 0                            2 6. 9 3      8 7. 8 4  
      6. 0 0 0        2 6. 7 0                            7 6. 3 3      3 3 8. 8 
      8. 0 0 0        4 4. 1 0                            1 4 7. 1      8 5 1. 8  
      1 2. 0 0        6 3. 6 0                            3 6 2. 5      3 0 8 4.  
      1 6. 0 0        8 1. 2 0                            6 5 2. 1      7 2 0 9.  
      2 4. 0 0        1 2 2. 0                            1 4 6 5. 2. 4 1 2 e + 0 0 4  
      3 6. 0 0        1 0 8. 0                            2 8 4 3. 6. 5 3 0 e + 0 0 4  
      4 8. 0 0        1 2 6. 0                            4 2 4 7. 1. 2 4 9 e + 0 0 5  
      6 0. 0 0        9 9. 1 0                            5 5 9 1. 1. 9 7 2 e + 0 0 5  
Pa ge 1 9 1 of 3 3 1
PI
PI


      7 2. 7 3        8 9. 6 0                            6 7 9 2. 2. 7 6 7 e + 0 0 5  
      9 6. 0 3        7 4. 4 0                            8 6 9 7. 4. 3 6 8 e + 0 0 5  
      1 2 0. 0 *      5 2. 4 0      5 0. 1 9      2. 2 1 0 1. 0 2 0 e + 0 0 4 5. 9 8 2 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      2 3. 8 0      2 5. 9 4     -2. 1 4 3 1. 1 0 7 e + 0 0 4 7. 1 1 6 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      1 4. 0 0      1 3. 4 1     0. 5 9 0 6 1. 1 5 1 e + 0 0 4 7. 8 0 3 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 8 7 4  
R s q _ a dj u st e d                                              0. 9 7 4 7  
C orr _ X Y                                                  -0. 9 9 3 7  
N o _ p oi nt s _l a m b d a _ z                                        3  
L a m b d a _ z                                1/ h               0. 0 2 7 5  
L a m b d a _ z _l o w er                            h             1 2 0. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              2 5. 2 0 8 2  
Tl a g                                      h               1. 0 1 6 7  
T m a x                                      h              4 8. 0 0 0 0  
C m a x                                  n g/ m L             1 2 6. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 2 8 0 0  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L              1 4. 0 0 0 0  
A U Cl a st                             h* n g/ m L           1 1 5 1 3. 9 4 3 8  
A U C all                              h* n g/ m L           1 1 5 1 3. 9 4 3 8  
A U CI N F _ o b s                          h* n g/ m L           1 2 0 2 3. 0 9 2 8  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              2 6. 7 1 8 0  
A U C _ % E xtr a p _ o b s                           %               4. 2 3 4 8  
V z _ F _ o b s                                  L            1 3 6 1. 1 7 2 7  
Cl _ F _ o b s                                L/ h              3 7. 4 2 8 0  
A U CI N F _ pr e d                         h* n g/ m L           1 2 0 0 1. 6 1 5 2  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              2 6. 6 7 0 3  
A U C _ % E xtr a p _ pr e d                          %               4. 0 6 3 4  
V z _ F _ pr e d                                 L            1 3 6 3. 6 0 8 6  
Cl _ F _ pr e d                               L/ h              3 7. 4 9 5 0  
A U M Cl a st                          h* h* n g/ m L          7 8 0 3 2 6. 2 1 9 8  
A U M CI N F _ o b s                       h* h* n g/ m L          8 8 4 3 7 9. 8 8 6 0  
A U M C _ % E xtr a p _ o b s                          %              1 1. 7 6 5 7  
A U M CI N F _ pr e d                      h* h* n g/ m L          8 7 9 9 9 0. 5 6 5 2  
A U M C _ % E xtr a p _ pr e d                         %              1 1. 3 2 5 6  
M R Tl a st                                   h              6 7. 7 7 2 3  
M R TI N F _ o b s                                h              7 3. 5 5 6 8  
M R TI N F _ pr e d                               h              7 3. 3 2 2 7  
A U C 0 _ 2 4                             h* n g/ m L            1 4 6 4. 9 3 0 8  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 0  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v a ti o n s:   2 2 
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
Pa ge 1 9 2 of 3 3 1
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Summary Table 
------------- 
      Time         Conc.      Pred.    Residual      AUC       AUMC      Weight 
          h       ng/mL       ng/mL       ng/mL     h*ng/mL   h*h*ng/mL 
------------------------------------------------------------------------------- 
     0.0000       0.0000                           0.0000     0.0000 
     0.2500       0.0000                           0.0000     0.0000 
     0.5000       0.0000                           0.0000     0.0000 
     0.7500       0.0000                           0.0000     0.0000 
      1.033       0.0000                           0.0000     0.0000 
      1.500       0.6450                           0.1505     0.2258 
      2.000        1.520                           0.6918      1.228 
      3.000        4.330                            3.617      9.243 
      4.000        6.680                            9.122      29.10 
      6.000        20.90                            36.70      181.2 
      8.000        32.40                            90.00      565.8 
      12.00        46.10                            247.0      2191. 
      16.00        53.70                            446.6      5015. 
      24.00        81.30                            986.6 1.626e+004 
      36.00        81.40                            1963. 4.555e+004 
      48.02        74.00                            2896. 8.465e+004 
      60.00        53.80                            3655. 1.254e+005 
      72.00        51.40                            4286. 1.670e+005 
      96.00        39.30                            5368. 2.573e+005 
      120.0 *      29.30      28.70     0.5974      6185. 3.451e+005      1.000 
      144.0 *      16.80      17.51    -0.7066      6725. 4.157e+005      1.000 
      168.0 *      10.90      10.68     0.2222      7052. 4.665e+005      1.000 
 
 
*) Starred values were included in the estimation of Lambda_z. 
 
 
Final Parameters 
--------------- 
Rsq                                                       0.9948 
Rsq_adjusted                                              0.9896 
Corr_XY                                                  -0.9974 
No_points_lambda_z                                        3 
Lambda_z                                1/h               0.0206 
Lambda_z_lower                            h             120.0000 
Lambda_z_upper                            h             168.0000 
HL_Lambda_z                               h              33.6471 
Tlag                                      h               1.0333 
Tmax                                      h              36.0000 
Cmax                                  ng/mL              81.4000 
Cmax_D                             ng/mL/mg               0.1809 
Tlast                                     h             168.0000 
Clast                                 ng/mL              10.9000 
AUClast                             h*ng/mL            7052.1211 
AUCall                              h*ng/mL            7052.1211 
AUCINF_obs                          h*ng/mL            7581.2341 
AUCINF_D_obs                     h*ng/mL/mg              16.8472 
AUC_%Extrap_obs                           %               6.9792 
Vz_F_obs                                  L            2881.3401 
Cl_F_obs                                L/h              59.3571 
AUCINF_pred                         h*ng/mL            7570.4465 
AUCINF_D_pred                    h*ng/mL/mg              16.8232 
AUC_%Extrap_pred                          %               6.8467 
Vz_F_pred                                 L            2885.4459 
Cl_F_pred                               L/h              59.4417 
AUMClast                          h*h*ng/mL          466513.1248 
AUMCINF_obs                       h*h*ng/mL          581088.5597 
AUMC_%Extrap_obs                          %              19.7174 
AUMCINF_pred                      h*h*ng/mL          578752.5900 
AUMC_%Extrap_pred                         %              19.3933 
MRTlast                                   h              66.1522 
MRTINF_obs                                h              76.6483 
MRTINF_pred                               h              76.4489 
AUC0_24                             h*ng/mL             986.6018 
 
 
 
WinNonlin 7.0.0.2535 
Page 193 of 331


P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 1  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:       0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 6 6 7       0. 5 1 9 0                          0. 0 6 9 2 0    0. 0 5 3 0 5  
      1. 0 0 0        1. 0 2 0                           0. 2 4 8 8     0. 2 1 8 5  
      1. 5 0 0        4. 7 6 0                            1. 6 9 4      2. 2 5 8  
      2. 0 0 0        7. 3 4 0                            4. 7 1 9      7. 7 1 3  
      3. 0 0 0        1 6. 7 0                            1 6. 7 4      4 0. 1 0  
      4. 0 0 0        2 4. 6 0                            3 7. 3 9      1 1 4. 4  
      6. 0 0 0        2 8. 4 0                            9 0. 3 9      3 8 3. 2  
      8. 0 1 7        4 2. 0 0                            1 6 1. 4      8 9 4. 5  
      1 2. 0 0        5 2. 6 0                            3 4 9. 8      2 8 2 2.  
      1 6. 0 0        7 8. 6 0                            6 1 2. 2      6 6 0 0.  
      2 4. 0 2        1 3 9. 0                            1 4 8 4. 2. 5 0 2 e + 0 0 4  
      3 6. 0 0        8 9. 0 0                            2 8 2 8. 6. 4 7 5 e + 0 0 4  
      4 8. 0 0        1 2 2. 0                            4 0 9 4. 1. 1 9 1 e + 0 0 5  
      6 0. 0 0        7 6. 7 0                            5 2 6 6. 1. 8 1 8 e + 0 0 5  
      7 2. 0 0        8 6. 4 0                            6 2 4 4. 2. 4 6 8 e + 0 0 5  
      9 6. 0 0 *      6 2. 3 0      6 2. 6 9    -0. 3 9 2 6      8 0 1 3. 3. 9 4 2 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      3 4. 8 0      3 4. 9 8    -0. 1 8 2 2      9 1 4 6. 5. 1 5 3 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      2 0. 1 0      1 9. 5 2     0. 5 8 0 1      9 7 8 9. 5. 9 9 4 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      1 0. 7 0      1 0. 8 9    -0. 1 9 2 0 1. 0 1 5 e + 0 0 4 6. 5 4 8 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 9 3  
R s q _ a dj u st e d                                              0. 9 9 8 9  
C orr _ X Y                                                  -0. 9 9 9 6  
N o _ p oi nt s _l a m b d a _ z                                        4  
L a m b d a _ z                                1/ h               0. 0 2 4 3  
L a m b d a _ z _l o w er                            h              9 6. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              2 8. 5 1 4 5  
Tl a g                                      h               0. 5 0 0 0  
T m a x                                      h              2 4. 0 1 6 7  
C m a x                                  n g/ m L             1 3 9. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 3 0 8 9  
Tl a st                                      h              1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L              1 0. 7 0 0 0  
A U Cl a st                             h* n g/ m L           1 0 1 4 6. 7 4 7 1  
A U C all                              h* n g/ m L           1 0 1 4 6. 7 4 7 1  
A U CI N F _ o b s                          h* n g/ m L           1 0 5 8 6. 9 2 1 6  
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A U CI N F _ D _ o b s                     h* n g/ m L/ m g              2 3. 5 2 6 5  
A U C _ % E x tr a p _ o b s                           %               4. 1 5 7 7 
V z _ F _ o b s                                  L            1 7 4 8. 5 7 3 4  
Cl _ F _ o b s                                L/ h              4 2. 5 0 5 3  
A U CI N F _ pr e d                         h* n g/ m L           1 0 5 9 4. 8 1 9 8  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              2 3. 5 4 4 0  
A U C _ % E xtr a p _ pr e d                          %               4. 2 2 9 2  
V z _ F _ pr e d                                 L            1 7 4 7. 2 6 9 9  
Cl _ F _ pr e d                               L/ h              4 2. 4 7 3 6  
A U M Cl a st                          h* h* n g/ m L          6 5 4 7 7 1. 4 9 1 4  
A U M CI N F _ o b s                       h* h* n g/ m L          7 4 6 8 2 8. 6 0 6 0  
A U M C _ % E xtr a p _ o b s                          %              1 2. 3 2 6 4  
A U M CI N F _ pr e d                      h* h* n g/ m L          7 4 8 4 8 0. 4 1 8 0  
A U M C _ % E xtr a p _ pr e d                         %              1 2. 5 1 9 9  
M R Tl a st                                    h              6 4. 5 3 0 2  
M R TI N F _ o b s                                h              7 0. 5 4 2 6  
M R TI N F _ pr e d                               h              7 0. 6 4 5 9  
A U C 0 _ 2 4                             h* n g/ m L            1 4 8 2. 0 8 4 8  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D =
, A P E RI O D = 1, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3 
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 0  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 5 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      2. 0 1 7       0. 9 7 2 0                           0. 2 5 1 1     0. 5 0 6 4  
      3. 0 0 0        2. 5 1 0                            1. 9 6 3      5. 1 7 2  
      4. 0 0 0        4. 5 8 0                            5. 5 0 8      1 8. 1 0  
      6. 0 0 0        1 0. 6 0                            2 0. 6 9      1 0 0. 0  
      8. 0 0 0        2 0. 5 0                            5 1. 7 9      3 2 7. 6  
      1 2. 0 0        4 0. 1 0                            1 7 3. 0      1 6 1 8.  
      1 6. 0 0        6 1. 7 0                            3 7 6. 6      4 5 5 5.  
      2 4. 0 0        1 0 8. 0                            1 0 5 5. 1. 8 8 7 e + 0 0 4  
      3 6. 0 0        1 2 4. 0                            2 4 4 7. 6. 1 2 1 e + 0 0 4  
      4 8. 0 0        1 5 0. 0                            4 0 9 1. 1. 3 1 2 e + 0 0 5  
      6 0. 0 0        1 0 8. 0                            5 6 2 6. 2. 1 3 5 e + 0 0 5  
      7 2. 0 0 *      1 0 0. 0      1 0 6. 1     -6. 1 0 1      6 8 7 3. 2. 9 5 8 e + 0 0 5      1. 0 0 0 
      9 6. 0 7 *      6 9. 7 0      6 7. 1 6      2. 5 3 8      8 8 9 3. 4. 6 4 1 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      4 3. 2 0      4 2. 6 2     0. 5 7 8 7 1. 0 2 2 e + 0 0 4 6. 0 6 0 e + 0 0 5      1. 0 0 0  
      1 4 4. 1 *      2 9. 7 0      2 6. 9 5      2. 7 4 6 1. 1 0 9 e + 0 0 4 7. 2 0 1 e + 0 0 5      1. 0 0 0  
      1 6 8. 6 *      1 5. 5 0      1 6. 9 3     -1. 4 3 3 1. 1 6 2 e + 0 0 4 8. 0 3 0 e + 0 0 5      1. 0 0 0  
 
 
Pa ge 1 9 5 of 3 3 1
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*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 8 9 5  
R s q _ a dj u st e d                                              0. 9 8 6 0  
C orr _ X Y                                                  -0. 9 9 4 7  
N o _ p oi nt s _l a m b d a _ z                                        5  
L a m b d a _ z                                1/ h               0. 0 1 9 0  
L a m b d a _ z _l o w er                            h              7 2. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 5 8 3 3  
H L _ L a m b d a _ z                               h              3 6. 4 8 0 1  
Tl a g                                      h               1. 5 0 0 0  
T m a x                                      h              4 8. 0 0 0 0  
C m a x                                  n g/ m L             1 5 0. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 3 3 3 3  
Tl a st                                     h             1 6 8. 5 8 3 3  
Cl a st                                 n g/ m L              1 5. 5 0 0 0  
A U Cl a st                             h* n g/ m L           1 1 6 2 2. 1 7 9 1  
A U C all                              h* n g/ m L           1 1 6 2 2. 1 7 9 1  
A U CI N F _ o b s                          h* n g/ m L           1 2 4 3 7. 9 3 8 2  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              2 7. 6 3 9 9  
A U C _ % E xtr a p _ o b s                           %               6. 5 5 8 6  
V z _ F _ o b s                                  L            1 9 0 4. 1 2 0 1  
Cl _ F _ o b s                                L/ h              3 6. 1 7 9 6  
A U CI N F _ pr e d                         h* n g/ m L           1 2 5 1 3. 3 3 0 5  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              2 7. 8 0 7 4  
A U C _ % E xtr a p _ pr e d                          %               7. 1 2 1 6  
V z _ F _ pr e d                                 L            1 8 9 2. 6 4 7 9  
Cl _ F _ pr e d                               L/ h              3 5. 9 6 1 6  
A U M Cl a st                          h* h* n g/ m L          8 0 2 9 6 6. 8 6 5 8  
A U M CI N F _ o b s                       h* h* n g/ m L          9 8 3 4 2 3. 3 4 1 5  
A U M C _ % E xtr a p _ o b s                          %              1 8. 3 4 9 8  
A U M CI N F _ pr e d                      h* h* n g/ m L         1 0 0 0 1 0 1. 1 0 8 5  
A U M C _ % E xtr a p _ pr e d                         %              1 9. 7 1 1 4  
M R Tl a st                                   h              6 9. 0 8 9 2  
M R TI N F _ o b s                                h              7 9. 0 6 6 4  
M R TI N F _ pr e d                               h              7 9. 9 2 2 9  
A U C 0 _ 2 4                             h* n g/ m L            1 0 5 5. 3 8 8 1  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 2  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                            0. 0 0 0 0     0. 0 0 0 0  
     0. 2 6 6 7       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
Pa ge 1 9 6 of 3 3 1
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     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 9 3 3 0                           0. 1 1 6 6     0. 1 1 6 6  
      1. 5 0 0        2. 8 0 0                            1. 0 5 0      1. 4 0 0  
      2. 0 0 0        5. 8 3 0                            3. 2 0 7      5. 3 6 5  
      3. 0 0 0        1 2. 1 0                            1 2. 1 7      2 9. 3 4  
      4. 0 0 0        1 9. 8 0                            2 8. 1 2      8 7. 0 9  
      6. 0 0 0        2 8. 2 0                            7 6. 1 2      3 3 5. 5  
      8. 0 0 0        4 3. 6 0                            1 4 7. 9      8 5 3. 5  
      1 2. 0 0        5 0. 0 0                            3 3 5. 1      2 7 5 1.  
      1 6. 0 0        6 6. 5 0                            5 6 8. 1      6 0 7 9.  
      2 4. 0 0        8 4. 7 0                            1 1 7 3. 1. 8 4 7 e + 0 0 4  
      3 6. 0 0        7 1. 6 0                            2 1 0 9. 4. 6 3 8 e + 0 0 4  
      4 8. 0 0        8 2. 9 0                            3 0 3 6. 8. 5 7 2 e + 0 0 4  
      6 0. 0 0        4 7. 6 0                            3 7 9 9. 1. 2 6 5 e + 0 0 5  
      7 2. 0 0        5 2. 3 0                            4 3 9 8. 1. 6 6 3 e + 0 0 5  
      9 6. 0 0 *      2 4. 5 0      2 5. 1 6    -0. 6 6 2 9      5 2 7 8. 2. 3 8 8 e + 0 0 5      1. 0 0 0  
      1 2 0. 2 *      1 6. 2 0      1 5. 3 6     0. 8 4 4 6      5 7 6 3. 2. 9 0 8 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      9. 1 8 0      9. 4 2 8    -0. 2 4 8 1      6 0 5 8. 3. 2 9 4 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      5. 7 7 0      5. 7 7 1  -0. 0 0 1 0 5 6      6 2 3 4. 3. 5 6 7 e + 0 0 5      1. 0 0 0 
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 6 4  
R s q _ a dj u st e d                                              0. 9 9 4 7  
C orr _ X Y                                                  -0. 9 9 8 2  
N o _ p oi nt s _l a m b d a _ z                                        4  
L a m b d a _ z                                1/ h               0. 0 2 0 5  
L a m b d a _ z _l o w er                            h              9 6. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 3. 8 9 2 1  
Tl a g                                      h               0. 7 5 0 0  
T m a x                                      h              2 4. 0 0 0 0  
C m a x                                  n g/ m L              8 4. 7 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 1 8 8 2  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L               5. 7 7 0 0  
A U Cl a st                             h* n g/ m L            6 2 3 3. 8 5 4 4  
A U C all                              h* n g/ m L            6 2 3 3. 8 5 4 4  
A U CI N F _ o b s                          h* n g/ m L            6 5 1 5. 9 8 3 8  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              1 4. 4 8 0 0  
A U C _ % E xtr a p _ o b s                           %               4. 3 2 9 8  
V z _ F _ o b s                                  L            3 3 7 6. 7 9 8 1  
Cl _ F _ o b s                                L/ h              6 9. 0 6 0 9  
A U CI N F _ pr e d                         h* n g/ m L            6 5 1 6. 0 3 5 4  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              1 4. 4 8 0 1  
A U C _ % E xtr a p _ pr e d                          %               4. 3 3 0 6  
V z _ F _ pr e d                                 L            3 3 7 6. 7 7 1 3  
Cl _ F _ pr e d                               L/ h              6 9. 0 6 0 4  
A U M Cl a st                          h* h* n g/ m L          3 5 6 7 3 9. 5 5 2 9  
A U M CI N F _ o b s                       h* h* n g/ m L          4 1 7 9 3 2. 2 7 2 8  
A U M C _ % E xtr a p _ o b s                          %              1 4. 6 4 1 8  
A U M CI N F _ pr e d                      h* h* n g/ m L          4 1 7 9 4 3. 4 6 8 0  
A U M C _ % E xtr a p _ pr e d                         %              1 4. 6 4 4 1  
M R Tl a st                                   h              5 7. 2 2 6 2  
M R TI N F _ o b s                                h              6 4. 1 3 9 6  
M R TI N F _ pr e d                               h              6 4. 1 4 0 8  
A U C 0 _ 2 4                             h* n g/ m L            1 1 7 2. 9 2 2 4  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 1  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
Pa ge 1 9 7 of 3 3 1
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                                   7.0.0.2535 
                            Core Version 04Jun2007 
 
Settings 
-------- 
Model:  Plasma Data, Extravascular Administration 
Number of nonmissing observations:   22 
Dose time:      0.00 
Dose amount:      450.00 
Calculation method:  Linear Trapezoidal Rule for for Increasing Values, 
                     Log Trapezoidal Rule for Decreasing Values 
Weighting for lambda_z calculations:  Uniform weighting 
Lambda_z method:  Find best fit for lambda_z,  Log regression 
 
 
Summary Table 
------------- 
      Time         Conc.      Pred.    Residual      AUC       AUMC      Weight 
          h       ng/mL       ng/mL       ng/mL     h*ng/mL   h*h*ng/mL 
------------------------------------------------------------------------------- 
     0.0000       0.0000                           0.0000     0.0000 
     0.2500       0.0000                           0.0000     0.0000 
     0.5000       0.0000                           0.0000     0.0000 
     0.8167       0.0000                           0.0000     0.0000 
      1.017       0.0000                           0.0000     0.0000 
      1.500        1.280                           0.3093     0.4640 
      2.000        2.510                            1.257      2.199 
      3.000        8.480                            6.752      17.43 
      4.000        12.80                            17.39      55.75 
      6.000        21.60                            51.79      236.5 
      8.000        28.20                            101.6      591.7 
      12.00        47.10                            252.2      2173. 
      16.00        64.80                            476.0      5377. 
      24.00        103.0                            1147. 1.941e+004 
      36.00        122.0                            2497. 6.060e+004 
      48.00        147.0                            4111. 1.293e+005 
      60.00        126.0                            5746. 2.173e+005 
      72.00        128.0                            7270. 3.180e+005 
      96.00 *      94.20      94.68    -0.4829      9916. 5.386e+005      1.000 
      120.0 *      63.70      63.66    0.04323 1.179e+004 7.392e+005      1.000 
      144.0 *      43.40      42.80     0.6026 1.306e+004 9.058e+005      1.000 
      168.0 *      28.50      28.77    -0.2734 1.391e+004 1.038e+006      1.000 
 
 
*) Starred values were included in the estimation of Lambda_z. 
 
 
Final Parameters 
--------------- 
Rsq                                                       0.9996 
Rsq_adjusted                                              0.9994 
Corr_XY                                                  -0.9998 
No_points_lambda_z                                        4 
Lambda_z                                1/h               0.0165 
Lambda_z_lower                            h              96.0000 
Lambda_z_upper                            h             168.0000 
HL_Lambda_z                               h              41.9002 
Tlag                                      h               1.0167 
Tmax                                      h              48.0000 
Cmax                                  ng/mL             147.0000 
Cmax_D                             ng/mL/mg               0.3267 
Tlast                                     h             168.0000 
Clast                                 ng/mL              28.5000 
AUClast                             h*ng/mL           13906.6199 
AUCall                              h*ng/mL           13906.6199 
AUCINF_obs                          h*ng/mL           15629.4232 
AUCINF_D_obs                     h*ng/mL/mg              34.7321 
AUC_%Extrap_obs                           %              11.0228 
Vz_F_obs                                  L            1740.4454 
Cl_F_obs                                L/h              28.7918 
AUCINF_pred                         h*ng/mL           15645.9495 
AUCINF_D_pred                    h*ng/mL/mg              34.7688 
AUC_%Extrap_pred                          %              11.1168 
Page 198 of 331


V z _ F _ pr e d                                 L            1 7 3 8. 6 0 7 0  
Cl _ F _ pr e d                               L/ h              2 8. 7 6 1 4  
A U M Cl a st                          h* h* n g/ m L         1 0 3 7 7 4 9. 8 4 0 0  
A U M CI N F _ o b s                       h* h* n g/ m L         1 4 3 1 3 2 2. 9 3 3 2  
A U M C _ % E xtr a p _ o b s                          %              2 7. 4 9 7 2  
A U M CI N F _ pr e d                      h* h* n g/ m L         1 4 3 5 0 9 8. 3 5 7 0  
A U M C _ % E xtr a p _ pr e d                         %              2 7. 6 8 7 9  
M R Tl a st                                   h              7 4. 6 2 2 7  
M R TI N F _ o b s                                h              9 1. 5 7 8 7  
M R TI N F _ pr e d                               h              9 1. 7 2 3 3  
A U C 0 _ 2 4                             h* n g/ m L            1 1 4 7. 1 9 1 8  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 0  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v a ti o n s:   1 8 
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 7 4 8 0                          0. 0 9 3 5 0    0. 0 9 3 5 0  
      1. 5 0 0        1. 5 9 0                           0. 6 7 8 0     0. 8 7 6 8  
      2. 0 0 0        3. 2 3 0                            1. 8 8 3      3. 0 8 8  
      3. 0 0 0        8. 7 3 0                            7. 8 6 3      1 9. 4 1  
      4. 0 0 0        1 6. 4 0                            2 0. 4 3      6 5. 3 1  
      6. 0 0 0        2 5. 9 0                            6 2. 7 3      2 8 6. 3  
      8. 0 0 0        4 1. 2 0                            1 2 9. 8      7 7 1. 3  
      1 2. 0 0        4 8. 6 0                            3 0 9. 4      2 5 9 7.  
      1 6. 0 0        6 8. 1 0                            5 4 2. 8      5 9 4 3.  
      2 4. 0 0        7 6. 8 0                            1 1 2 2. 1. 7 6 7 e + 0 0 4  
      3 6. 0 0 *      6 1. 7 0      6 2. 2 2    -0. 5 2 2 9      1 9 5 0. 4. 2 3 2 e + 0 0 4      1. 0 0 0  
      4 8. 0 0 *      5 6. 3 0      5 2. 8 9      3. 4 0 8      2 6 5 8. 7. 1 9 7 e + 0 0 4      1. 0 0 0  
      6 0. 0 0 *      4 0. 7 0      4 4. 9 6     -4. 2 6 1      3 2 3 5. 1. 0 2 9 e + 0 0 5      1. 0 0 0  
      7 2. 0 0 *      4 0. 0 0      3 8. 2 2      1. 7 8 2      3 7 1 9. 1. 3 4 9 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 8 9 2 1  
R s q _ a dj u st e d                                              0. 8 3 8 2  
C orr _ X Y                                                  -0. 9 4 4 5  
N o _ p oi nt s _l a m b d a _ z                                        4  
L a m b d a _ z                                1/ h               0. 0 1 3 5  
L a m b d a _ z _l o w er                            h              3 6. 0 0 0 0  
Pa ge 1 9 9 of 3 3 1
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L a m b d a _ z _ u p p er                            h              7 2. 0 0 0 0  
H L _ L a m b d a _ z                               h              5 1. 1 9 6 3  
Tl a g                                      h               0. 7 5 0 0  
T m a x                                      h              2 4. 0 0 0 0  
C m a x                                  n g/ m L              7 6. 8 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 1 7 0 7  
Tl a st                                     h              7 2. 0 0 0 0  
Cl a st                                 n g/ m L              4 0. 0 0 0 0  
A U Cl a st                             h* n g/ m L            3 7 1 8. 7 6 5 5  
A U C all                              h* n g/ m L            3 7 1 8. 7 6 5 5  
A U CI N F _ o b s                          h* n g/ m L            6 6 7 3. 1 9 3 6  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              1 4. 8 2 9 3  
A U C _ % E xtr a p _ o b s                           %              4 4. 2 7 3 1  
V z _ F _ o b s                                  L            4 9 8 0. 7 2 1 2  
Cl _ F _ o b s                                L/ h              6 7. 4 3 4 0  
A U CI N F _ pr e d                         h* n g/ m L            6 5 4 1. 6 1 0 3  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              1 4. 5 3 6 9  
A U C _ % E xtr a p _ pr e d                          %              4 3. 1 5 2 1  
V z _ F _ pr e d                                 L            5 0 8 0. 9 0 7 5  
Cl _ F _ pr e d                               L/ h              6 8. 7 9 0 4  
A U M Cl a st                          h* h* n g/ m L          1 3 4 8 9 0. 2 7 4 2  
A U M CI N F _ o b s                       h* h* n g/ m L          5 6 5 8 2 5. 2 4 9 8  
A U M C _ % E xtr a p _ o b s                          %              7 6. 1 6 0 4  
A U M CI N F _ pr e d                      h* h* n g/ m L          5 4 6 6 3 2. 4 1 3 6  
A U M C _ % E xtr a p _ pr e d                         %              7 5. 3 2 3 4  
M R Tl a st                                    h              3 6. 2 7 2 9  
M R TI N F _ o b s                                h              8 4. 7 9 0 8  
M R TI N F _ pr e d                               h              8 3. 5 6 2 4  
A U C 0 _ 2 4                             h* n g/ m L            1 1 2 2. 4 2 8 0  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 2  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 5 3 3 0                          0. 0 6 6 6 3    0. 0 6 6 6 3  
      1. 5 0 0        1. 6 5 0                           0. 6 1 2 4     0. 8 1 8 6  
      2. 0 0 0        3. 1 4 0                            1. 8 1 0      3. 0 0 7  
      3. 0 0 0        8. 4 6 0                            7. 6 1 0      1 8. 8 4  
      4. 0 0 0        1 5. 5 0                            1 9. 5 9      6 2. 5 3  
      6. 0 0 0        2 4. 8 0                            5 9. 8 9      2 7 3. 3 
      8. 0 0 0        3 7. 0 0                            1 2 1. 7      7 1 8. 1  
      1 2. 0 0        4 9. 9 0                            2 9 5. 5      2 5 0 8.  
      1 6. 0 0        6 0. 7 0                            5 1 6. 7      5 6 4 8.  
Pa ge 2 0 0 of 3 3 1
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      2 4. 0 0        9 3. 9 0                            1 1 3 5. 1. 8 5 5 e + 0 0 4  
      3 6. 0 0        7 9. 6 0                            2 1 7 4. 4. 9 5 3 e + 0 0 4  
      4 8. 0 0        8 2. 0 0                            3 1 4 3. 9. 0 3 4 e + 0 0 4  
      6 0. 0 0        5 9. 5 0                            3 9 8 5. 1. 3 5 5 e + 0 0 5  
      7 2. 0 0        4 6. 6 0                            4 6 1 9. 1. 7 7 2 e + 0 0 5  
      9 6. 0 0 *      3 4. 8 0      3 3. 4 4      1. 3 6 0      5 5 8 8. 2. 5 8 1 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      1 4. 1 0      1 5. 8 7     -1. 7 7 2      6 1 3 8. 3. 1 6 5 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      8. 4 7 0      7. 5 3 3     0. 9 3 6 6      6 4 0 4. 3. 5 1 2 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      3. 4 4 0      3. 5 7 6    -0. 1 3 5 6      6 5 3 7. 3. 7 1 9 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 8 9 0  
R s q _ a dj u st e d                                              0. 9 8 3 5  
C orr _ X Y                                                  -0. 9 9 4 5  
N o _ p oi nt s _l a m b d a _ z                                        4  
L a m b d a _ z                                1/ h               0. 0 3 1 1  
L a m b d a _ z _l o w er                            h              9 6. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              2 2. 3 2 3 3  
Tl a g                                      h               0. 7 5 0 0  
T m a x                                      h              2 4. 0 0 0 0  
C m a x                                  n g/ m L              9 3. 9 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 2 0 8 7  
Tl a st                                      h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L               3. 4 4 0 0  
A U Cl a st                             h* n g/ m L            6 5 3 7. 4 9 2 0  
A U C all                              h* n g/ m L            6 5 3 7. 4 9 2 0  
A U CI N F _ o b s                          h* n g/ m L            6 6 4 8. 2 7 9 8  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              1 4. 7 7 4 0  
A U C _ % E xtr a p _ o b s                           %               1. 6 6 6 4  
V z _ F _ o b s                                  L            2 1 7 9. 9 0 1 3  
Cl _ F _ o b s                                L/ h              6 7. 6 8 6 7  
A U CI N F _ pr e d                         h* n g/ m L            6 6 5 2. 6 4 7 3  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              1 4. 7 8 3 7  
A U C _ % E xtr a p _ pr e d                          %               1. 7 3 1 0  
V z _ F _ pr e d                                 L            2 1 7 8. 4 7 0 2  
Cl _ F _ pr e d                               L/ h              6 7. 6 4 2 2  
A U M Cl a st                          h* h* n g/ m L          3 7 1 8 9 0. 3 1 1 0  
A U M CI N F _ o b s                       h* h* n g/ m L          3 9 4 0 7 0. 6 7 3 2  
A U M C _ % E xtr a p _ o b s                          %               5. 6 2 8 5  
A U M CI N F _ pr e d                      h* h* n g/ m L          3 9 4 9 4 5. 0 6 6 9  
A U M C _ % E xtr a p _ pr e d                         %               5. 8 3 7 5  
M R Tl a st                                    h              5 6. 8 8 5 8  
M R TI N F _ o b s                                h              5 9. 2 7 4 1  
M R TI N F _ pr e d                               h              5 9. 3 6 6 6  
A U C 0 _ 2 4                             h* n g/ m L            1 1 3 5. 0 8 9 9  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 1  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
Pa ge 2 0 1 of 3 3 1
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PI


Weighting for lambda_z calculations:  Uniform weighting 
Lambda_z method:  Find best fit for lambda_z,  Log regression 
 
 
Summary Table 
------------- 
      Time         Conc.      Pred.    Residual      AUC       AUMC      Weight 
          h       ng/mL       ng/mL       ng/mL     h*ng/mL   h*h*ng/mL 
------------------------------------------------------------------------------- 
     0.0000       0.0000                           0.0000     0.0000 
     0.2500       0.0000                           0.0000     0.0000 
     0.5000       0.0000                           0.0000     0.0000 
     0.7500       0.5460                          0.06825    0.05119 
      1.017        1.040                           0.2797     0.2468 
      1.500        2.250                            1.075      1.318 
      2.000        5.260                            2.952      4.792 
      3.000        11.40                            11.28      27.15 
      4.000        18.80                            26.38      81.85 
      6.000        31.40                            76.58      345.5 
      8.000        43.80                            151.8      884.3 
      12.00        54.60                            348.6      2895. 
      16.00        70.70                            599.2      6468. 
      24.02        101.0                            1287. 2.073e+004 
      36.00        95.50                            2464. 5.598e+004 
      48.00        121.0                            3763. 1.115e+005 
      60.00        84.40                            4983. 1.769e+005 
      72.00 *      89.10      93.24     -4.141      6024. 2.457e+005      1.000 
      96.00 *      62.20      57.75      4.450      7820. 3.953e+005      1.000 
      120.0 *      34.00      35.74     -1.745      8942. 5.152e+005      1.000 
      144.0 *      23.50      22.15      1.346      9623. 6.046e+005      1.000 
      168.1 *      13.20      13.71    -0.5077 1.005e+004 6.711e+005      1.000 
 
 
*) Starred values were included in the estimation of Lambda_z. 
 
 
Final Parameters 
--------------- 
Rsq                                                       0.9935 
Rsq_adjusted                                              0.9914 
Corr_XY                                                  -0.9968 
No_points_lambda_z                                        5 
Lambda_z                                1/h               0.0200 
Lambda_z_lower                            h              72.0000 
Lambda_z_upper                            h             168.0500 
HL_Lambda_z                               h              34.7254 
Tlag                                      h               0.5000 
Tmax                                      h              48.0000 
Cmax                                  ng/mL             121.0000 
Cmax_D                             ng/mL/mg               0.2689 
Tlast                                     h             168.0500 
Clast                                 ng/mL              13.2000 
AUClast                             h*ng/mL           10052.9042 
AUCall                              h*ng/mL           10052.9042 
AUCINF_obs                          h*ng/mL           10714.2004 
AUCINF_D_obs                     h*ng/mL/mg              23.8093 
AUC_%Extrap_obs                           %               6.1721 
Vz_F_obs                                  L            2104.1410 
Cl_F_obs                                L/h              42.0003 
AUCINF_pred                         h*ng/mL           10739.6332 
AUCINF_D_pred                    h*ng/mL/mg              23.8659 
AUC_%Extrap_pred                          %               6.3943 
Vz_F_pred                                 L            2099.1581 
Cl_F_pred                               L/h              41.9009 
AUMClast                          h*h*ng/mL          671148.9787 
AUMCINF_obs                       h*h*ng/mL          815409.5499 
AUMC_%Extrap_obs                          %              17.6918 
AUMCINF_pred                      h*h*ng/mL          820957.6704 
AUMC_%Extrap_pred                         %              18.2480 
MRTlast                                   h              66.7617 
MRTINF_obs                                h              76.1055 
MRTINF_pred                               h              76.4419 
AUC0_24                             h*ng/mL            1285.7303 
Page 202 of 331


 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 2  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      2. 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      3. 0 0 0        1. 6 9 0                           0. 8 4 5 0      2. 5 3 5  
      4. 0 0 0        4. 2 7 0                            3. 8 2 5      1 3. 6 1  
      6. 0 0 0        1 3. 9 0                            2 2. 0 0      1 1 4. 1  
      8. 0 0 0        1 9. 4 0                            5 5. 3 0      3 5 2. 7  
      1 2. 0 0        2 9. 2 0                            1 5 2. 5      1 3 6 4.  
      1 6. 0 0        3 6. 0 0                            2 8 2. 9      3 2 1 7.  
      2 4. 0 0        6 0. 7 0                            6 6 9. 7 1. 1 3 5 e + 0 0 4  
      3 6. 0 0        6 5. 9 0                            1 4 2 9. 3. 4 3 2 e + 0 0 4  
      4 8. 0 0        6 4. 8 0                            2 2 1 3. 6. 7 2 5 e + 0 0 4  
      6 0. 0 0        5 1. 3 0                            2 9 0 7. 1. 0 4 5 e + 0 0 5  
      7 2. 0 0 *      4 5. 8 0      4 6. 8 1     -1. 0 0 9      3 4 8 9. 1. 4 2 9 e + 0 0 5      1. 0 0 0  
      9 6. 0 0 *      2 7. 8 0      2 6. 1 1      1. 6 9 4      4 3 5 4. 2. 1 4 7 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      1 4. 8 0      1 4. 5 6     0. 2 4 0 5      4 8 4 9. 2. 6 7 5 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      7. 1 0 0      8. 1 2 0     -1. 0 2 0      5 1 0 1. 3. 0 0 4 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      4. 8 9 0      4. 5 2 9     0. 3 6 1 4      5 2 4 3. 3. 2 2 5 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 1 7  
R s q _ a dj u st e d                                              0. 9 8 8 9  
C orr _ X Y                                                  -0. 9 9 5 8  
N o _ p oi nt s _l a m b d a _ z                                        5  
L a m b d a _ z                                1/ h               0. 0 2 4 3  
L a m b d a _ z _l o w er                            h              7 2. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              2 8. 4 8 9 8  
Tl a g                                      h               2. 0 0 0 0  
T m a x                                      h              3 6. 0 0 0 0  
C m a x                                  n g/ m L              6 5. 9 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 1 4 6 4  
Tl a st                                      h             1 6 8. 0 0 0 0  
Pa ge 2 0 3 of 3 3 1
PI
PI


Cl a st                                 n g/ m L               4. 8 9 0 0  
A U Cl a st                             h* n g/ m L            5 2 4 2. 9 4 4 4  
A U C all                              h* n g/ m L            5 2 4 2. 9 4 4 4  
A U CI N F _ o b s                           h* n g/ m L            5 4 4 3. 9 3 3 4  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              1 2. 0 9 7 6  
A U C _ % E xtr a p _ o b s                           %               3. 6 9 2 0  
V z _ F _ o b s                                  L            3 3 9 7. 5 2 9 2  
Cl _ F _ o b s                                L/ h              8 2. 6 6 0 8  
A U CI N F _ pr e d                         h* n g/ m L            5 4 2 9. 0 8 0 8  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              1 2. 0 6 4 6  
A U C _ % E xtr a p _ pr e d                          %               3. 4 2 8 5  
V z _ F _ pr e d                                 L            3 4 0 6. 8 2 4 0  
Cl _ F _ pr e d                               L/ h              8 2. 8 8 7 0  
A U M Cl a st                          h* h* n g/ m L          3 2 2 4 5 6. 6 5 9 3  
A U M CI N F _ o b s                       h* h* n g/ m L          3 6 4 4 8 3. 8 7 6 4  
A U M C _ % E xtr a p _ o b s                          %              1 1. 5 3 0 6  
A U M CI N F _ pr e d                      h* h* n g/ m L          3 6 1 3 7 8. 1 6 8 9  
A U M C _ % E xtr a p _ pr e d                         %              1 0. 7 7 0 3  
M R Tl a st                                    h              6 1. 5 0 3 0  
M R TI N F _ o b s                                h              6 6. 9 5 2 3  
M R TI N F _ pr e d                               h              6 6. 5 6 3 4  
A U C 0 _ 2 4                             h* n g/ m L             6 6 9. 6 9 5 0  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 1  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 5 0 6 0                          0. 0 6 3 2 5    0. 0 6 3 2 5  
      1. 5 0 0        1. 7 8 0                           0. 6 3 4 8     0. 8 5 7 3  
      2. 0 0 0        4. 2 8 0                            2. 1 5 0      3. 6 6 5  
      3. 0 0 0        8. 8 9 0                            8. 7 3 5      2 1. 2 8  
      4. 0 0 0        1 6. 6 0                            2 1. 4 8      6 7. 8 1  
      6. 0 0 0        2 6. 4 0                            6 4. 4 8      2 9 2. 6  
      8. 0 1 7        3 7. 6 0                            1 2 9. 0      7 5 6. 3  
      1 2. 0 0        4 8. 5 0                            3 0 0. 5      2 5 1 6.  
      1 6. 0 0        6 2. 1 0                            5 2 1. 7      5 6 6 7.  
      2 4. 0 0        9 4. 4 0                            1 1 4 8. 1. 8 7 0 e + 0 0 4  
      3 6. 0 0        8 2. 0 0                            2 2 0 4. 5. 0 2 5 e + 0 0 4  
      4 8. 0 0        1 1 7. 0                            3 3 9 8. 1. 0 1 7 e + 0 0 5  
      6 0. 0 3        1 1 0. 0                            4 7 6 4. 1. 7 5 3 e + 0 0 5  
      7 2. 0 0 *      1 0 9. 0      1 0 9. 7    -0. 7 4 5 7      6 0 7 4. 2. 6 1 8 e + 0 0 5      1. 0 0 0  
      9 6. 0 3 *      6 9. 8 0      6 9. 6 7     0. 1 2 7 2      8 1 8 8. 4. 3 7 5 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      4 4. 1 0      4 4. 2 9    -0. 1 8 8 0      9 5 2 9. 5. 8 1 2 e + 0 0 5      1. 0 0 0  
Pa ge 2 0 4 of 3 3 1
PI
PI


      1 4 4. 0 *      2 9. 0 0      2 8. 1 3     0. 8 6 5 7 1. 0 3 9 e + 0 0 4 6. 9 4 6 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      1 7. 5 0      1 7. 8 7    -0. 3 7 2 5 1. 0 9 4 e + 0 0 4 7. 7 9 3 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 9 3  
R s q _ a dj u st e d                                              0. 9 9 9 1  
C orr _ X Y                                                  -0. 9 9 9 7  
N o _ p oi nt s _l a m b d a _ z                                        5  
L a m b d a _ z                                1/ h               0. 0 1 8 9  
L a m b d a _ z _l o w er                            h              7 2. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 6. 6 6 4 3  
Tl a g                                      h               0. 7 5 0 0  
T m a x                                      h              4 8. 0 0 0 0  
C m a x                                  n g/ m L             1 1 7. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 2 6 0 0  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                  n g/ m L              1 7. 5 0 0 0  
A U Cl a st                             h* n g/ m L           1 0 9 4 0. 1 6 9 4  
A U C all                              h* n g/ m L           1 0 9 4 0. 1 6 9 4  
A U CI N F _ o b s                          h* n g/ m L           1 1 8 6 5. 8 3 8 2  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              2 6. 3 6 8 5  
A U C _ % E xtr a p _ o b s                           %               7. 8 0 1 1  
V z _ F _ o b s                                  L            2 0 0 6. 0 0 3 5  
Cl _ F _ o b s                                L/ h              3 7. 9 2 4 0  
A U CI N F _ pr e d                         h* n g/ m L           1 1 8 8 5. 5 4 0 3  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              2 6. 4 1 2 3  
A U C _ % E xtr a p _ pr e d                          %               7. 9 5 4 0  
V z _ F _ pr e d                                 L            2 0 0 2. 6 7 8 2  
Cl _ F _ pr e d                               L/ h              3 7. 8 6 1 1  
A U M Cl a st                          h* h* n g/ m L          7 7 9 2 9 2. 5 9 0 3  
A U M CI N F _ o b s                       h* h* n g/ m L          9 8 3 7 6 8. 5 4 1 8  
A U M C _ % E xtr a p _ o b s                          %              2 0. 7 8 5 0  
A U M CI N F _ pr e d                      h* h* n g/ m L          9 8 8 1 2 0. 6 5 1 3  
A U M C _ % E xtr a p _ pr e d                         %              2 1. 1 3 3 9  
M R Tl a st                                   h              7 1. 2 3 2 2  
M R TI N F _ o b s                                h              8 2. 9 0 7 6  
M R TI N F _ pr e d                               h              8 3. 1 3 6 4  
A U C 0 _ 2 4                             h* n g/ m L            1 1 4 7. 6 9 5 6  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 2  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
Pa ge 2 0 5 of 3 3 1
PI
PI


          h       n g/ m L        n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 8 1 6 7       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 1 7       0. 5 1 1 0                          0. 0 5 1 1 0    0. 0 5 1 9 5  
      1. 5 0 0        1. 4 5 0                           0. 5 2 5 0     0. 7 0 3 1  
      2. 0 0 0        3. 0 4 0                            1. 6 4 8      2. 7 6 7  
      3. 0 0 0        9. 9 9 0                            8. 1 6 3      2 0. 7 9  
      4. 0 0 0        1 8. 0 0                            2 2. 1 6      7 1. 7 8  
      6. 0 0 0        2 5. 1 0                            6 5. 2 6      2 9 4. 4  
      8. 0 3 3        3 9. 9 0                            1 3 1. 3      7 7 3. 4  
      1 2. 0 0        4 9. 7 0                            3 0 9. 0      2 5 9 2.  
      1 6. 0 0        7 2. 1 0                            5 5 2. 6      6 0 9 2.  
      2 4. 0 0        8 1. 4 0                            1 1 6 7. 1. 8 5 2 e + 0 0 4  
      3 6. 0 0 *      7 1. 3 0      7 6. 8 4     -5. 5 4 4      2 0 8 2. 4. 5 8 5 e + 0 0 4      1. 0 0 0  
      4 8. 0 2 *      7 0. 4 0      6 1. 5 6      8. 8 4 0      2 9 3 3. 8. 1 6 0 e + 0 0 4      1. 0 0 0  
      6 0. 0 8 *      4 9. 6 0      4 9. 2 7     0. 3 2 9 5      3 6 5 0. 1. 2 0 1 e + 0 0 5      1. 0 0 0  
      7 2. 0 0 *      4 2. 3 0      3 9. 5 4      2. 7 5 6      4 1 9 6. 1. 5 6 1 e + 0 0 5      1. 0 0 0  
      9 5. 7 3 *      2 3. 7 0      2 5. 5 2     -1. 8 1 9      4 9 5 8. 2. 1 9 1 e + 0 0 5      1. 0 0 0  
      1 2 0. 1 *      1 3. 3 0      1 6. 2 7     -2. 9 6 7      5 3 9 7. 2. 6 6 0 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      1 1. 3 0      1 0. 4 7     0. 8 2 8 2      5 6 9 0. 3. 0 4 6 e + 0 0 5      1. 0 0 0  
      1 7 1. 8 *      6. 7 0 0      6. 2 7 3     0. 4 2 6 9      5 9 3 5. 3. 4 2 9 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 8 5 1  
R s q _ a dj u st e d                                              0. 9 8 2 6  
C orr _ X Y                                                  -0. 9 9 2 5  
N o _ p oi nt s _l a m b d a _ z                                        8  
L a m b d a _ z                                1/ h               0. 0 1 8 5  
L a m b d a _ z _l o w er                            h              3 6. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 7 1. 7 6 6 7  
H L _ L a m b d a _ z                               h              3 7. 5 5 9 8  
Tl a g                                      h               0. 8 1 6 7  
T m a x                                      h              2 4. 0 0 0 0  
C m a x                                  n g/ m L              8 1. 4 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 1 8 0 9  
Tl a st                                     h             1 7 1. 7 6 6 7  
Cl a st                                 n g/ m L               6. 7 0 0 0  
A U Cl a st                             h* n g/ m L            5 9 3 4. 5 1 8 5  
A U C all                              h* n g/ m L            5 9 3 4. 5 1 8 5  
A U CI N F _ o b s                          h* n g/ m L            6 2 9 7. 5 7 3 3  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              1 3. 9 9 4 6  
A U C _ % E xtr a p _ o b s                           %               5. 7 6 5 0  
V z _ F _ o b s                                  L            3 8 7 2. 0 1 1 5  
Cl _ F _ o b s                                L/ h              7 1. 4 5 6 1  
A U CI N F _ pr e d                         h* n g/ m L            6 2 7 4. 4 3 8 3  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              1 3. 9 4 3 2  
A U C _ % E xtr a p _ pr e d                          %               5. 4 1 7 5  
V z _ F _ pr e d                                 L            3 8 8 6. 2 8 8 3  
Cl _ F _ pr e d                               L/ h              7 1. 7 1 9 6  
A U M Cl a st                          h* h* n g/ m L          3 4 2 8 9 5. 3 1 9 3  
A U M CI N F _ o b s                       h* h* n g/ m L          4 2 4 9 2 8. 9 7 9 3  
A U M C _ % E xtr a p _ o b s                          %              1 9. 3 0 5 3  
A U M CI N F _ pr e d                      h* h* n g/ m L          4 1 9 7 0 1. 5 4 2 7  
A U M C _ % E xtr a p _ pr e d                         %              1 8. 3 0 0 2  
M R Tl a st                                   h              5 7. 7 7 9 8  
M R TI N F _ o b s                                h              6 7. 4 7 5 0  
M R TI N F _ pr e d                               h              6 6. 8 9 0 7  
A U C 0 _ 2 4                             h* n g/ m L            1 1 6 6. 6 4 7 5  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
Pa ge 2 0 6 of 3 3 1
PI
PI


                                                  Time:     09:24:12 
 
 
                  WINNONLIN NONCOMPARTMENTAL ANALYSIS PROGRAM 
                                   7.0.0.2535 
                            Core Version 04Jun2007 
 
Settings 
-------- 
Model:  Plasma Data, Extravascular Administration 
Number of nonmissing observations:   22 
Dose time:      0.00 
Dose amount:      450.00 
Calculation method:  Linear Trapezoidal Rule for for Increasing Values, 
                     Log Trapezoidal Rule for Decreasing Values 
Weighting for lambda_z calculations:  Uniform weighting 
Lambda_z method:  Find best fit for lambda_z,  Log regression 
 
 
Summary Table 
------------- 
      Time         Conc.      Pred.    Residual      AUC       AUMC      Weight 
          h       ng/mL       ng/mL       ng/mL     h*ng/mL   h*h*ng/mL 
------------------------------------------------------------------------------- 
     0.0000       0.0000                           0.0000     0.0000 
     0.2500       0.0000                           0.0000     0.0000 
     0.5000       0.0000                           0.0000     0.0000 
     0.7500       0.6250                          0.07813    0.05859 
      1.000       0.7490                           0.2499     0.2108 
      1.500        1.910                           0.9146      1.114 
      2.000        3.430                            2.250      3.546 
      3.000        9.020                            8.475      20.51 
      4.000        17.00                            21.48      68.04 
      6.000        27.60                            66.08      301.6 
      8.000        42.70                            136.4      808.8 
      12.00        61.40                            344.6      2966. 
      16.00        81.40                            630.2      7044. 
      24.02        129.0                            1474. 2.468e+004 
      36.00        120.0                            2965. 6.933e+004 
      48.00        150.0                            4585. 1.384e+005 
      60.00        126.0                            6237. 2.274e+005 
      72.00        148.0                            7881. 3.367e+005 
      96.00 *      114.0      114.8    -0.7664 1.101e+004 5.976e+005      1.000 
      120.0 *      77.90      74.86      3.043 1.328e+004 8.416e+005      1.000 
      144.0 *      46.00      48.83     -2.825 1.474e+004 1.032e+006      1.000 
      168.0 *      32.70      31.85     0.8537 1.567e+004 1.177e+006      1.000 
 
 
*) Starred values were included in the estimation of Lambda_z. 
 
 
Final Parameters 
--------------- 
Rsq                                                       0.9936 
Rsq_adjusted                                              0.9904 
Corr_XY                                                  -0.9968 
No_points_lambda_z                                        4 
Lambda_z                                1/h               0.0178 
Lambda_z_lower                            h              96.0000 
Lambda_z_upper                            h             168.0000 
HL_Lambda_z                               h              38.9294 
Tlag                                      h               0.5000 
Tmax                                      h              48.0000 
Cmax                                  ng/mL             150.0000 
Cmax_D                             ng/mL/mg               0.3333 
Tlast                                     h             168.0000 
Clast                                 ng/mL              32.7000 
AUClast                             h*ng/mL           15670.9617 
AUCall                              h*ng/mL           15670.9617 
AUCINF_obs                          h*ng/mL           17507.5010 
AUCINF_D_obs                     h*ng/mL/mg              38.9056 
AUC_%Extrap_obs                           %              10.4900 
Vz_F_obs                                  L            1443.5799 
Page 207 of 331


Cl _ F _ o b s                                L/ h              2 5. 7 0 3 3  
A U CI N F _ pr e d                         h* n g/ m L           1 7 4 5 9. 5 5 5 9  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              3 8. 7 9 9 0  
A U C _ % E xtr a p _ pr e d                          %              1 0. 2 4 4 2  
V z _ F _ pr e d                                 L            1 4 4 7. 5 4 4 0  
Cl _ F _ pr e d                               L/ h              2 5. 7 7 3 9  
A U M Cl a st                          h* h* n g/ m L         1 1 7 7 2 3 3. 9 4 2 8  
A U M CI N F _ o b s                       h* h* n g/ m L         1 5 8 8 9 1 8. 6 0 9 6  
A U M C _ % E xtr a p _ o b s                          %              2 5. 9 0 9 7  
A U M CI N F _ pr e d                      h* h* n g/ m L         1 5 7 8 1 7 1. 0 7 0 1  
A U M C _ % E xtr a p _ pr e d                         %              2 5. 4 0 5 2  
M R Tl a st                                   h              7 5. 1 2 2 0  
M R TI N F _ o b s                                h              9 0. 7 5 6 4  
M R TI N F _ pr e d                               h              9 0. 3 9 0 1  
A U C 0 _ 2 4                             h* n g/ m L            1 4 7 1. 3 8 8 8  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 2  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     Lo g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0       0. 5 1 2 0                           0. 1 2 8 0     0. 1 9 2 0  
      2. 0 0 0        1. 0 6 0                           0. 5 2 1 0     0. 9 1 4 0  
      3. 0 0 0        3. 0 5 0                            2. 5 7 6      6. 5 4 9  
      4. 0 0 0        8. 2 7 0                            8. 2 3 6      2 7. 6 6  
      6. 0 0 0        1 9. 4 0                            3 5. 9 1      1 7 7. 1  
      8. 0 0 0        3 2. 4 0                            8 7. 7 1      5 5 2. 7  
      1 2. 0 3        5 3. 6 0                            2 6 1. 1      2 3 7 6.  
      1 6. 0 0        7 2. 5 0                            5 1 1. 2      5 9 5 6.  
      2 4. 0 0        1 0 7. 0                            1 2 2 9. 2. 0 8 7 e + 0 0 4  
      3 6. 0 0        1 0 2. 0                            2 4 8 3. 5. 8 4 2 e + 0 0 4  
      4 8. 0 0        1 2 3. 0                            3 8 3 3. 1. 1 5 9 e + 0 0 5  
      6 0. 0 0        7 6. 9 0                            5 0 1 1. 1. 7 8 9 e + 0 0 5  
      7 2. 0 0 *      7 3. 5 0      7 2. 1 2      1. 3 7 7      5 9 1 3. 2. 3 8 4 e + 0 0 5      1. 0 0 0  
      9 6. 0 7 *      4 4. 2 0      4 1. 7 3      2. 4 7 3      7 3 0 0. 3. 5 3 5 e + 0 0 5      1. 0 0 0  
      1 2 0. 1 *      2 3. 1 0      2 4. 1 9     -1. 0 8 7      8 0 8 0. 4. 3 6 8 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      1 2. 0 0      1 4. 0 3     -2. 0 3 1      8 4 8 5. 4. 8 9 9 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      9. 2 2 0      8. 1 3 0      1. 0 9 0      8 7 3 9. 5. 2 9 2 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Pa ge 2 0 8 of 3 3 1
PI
PI


Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 8 4 8  
R s q _ a dj u st e d                                              0. 9 7 9 7  
C orr _ X Y                                                  -0. 9 9 2 4  
N o _ p oi nt s _l a m b d a _ z                                        5  
L a m b d a _ z                                1/ h               0. 0 2 2 7  
L a m b d a _ z _l o w er                            h              7 2. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 0. 4 8 4 3  
Tl a g                                      h               1. 0 0 0 0  
T m a x                                      h              4 8. 0 0 0 0  
C m a x                                  n g/ m L             1 2 3. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 2 7 3 3  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L               9. 2 2 0 0  
A U Cl a st                             h* n g/ m L            8 7 3 8. 5 9 6 2  
A U C all                              h* n g/ m L            8 7 3 8. 5 9 6 2  
A U CI N F _ o b s                          h* n g/ m L            9 1 4 4. 0 8 7 0  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              2 0. 3 2 0 2  
A U C _ % E xtr a p _ o b s                           %               4. 4 3 4 5  
V z _ F _ o b s                                  L            2 1 6 4. 3 2 3 8  
Cl _ F _ o b s                                L/ h              4 9. 2 1 2 1  
A U CI N F _ pr e d                         h* n g/ m L            9 0 9 6. 1 4 0 9  
A U CI N F _ D _ pr e d                     h* n g/ m L/ m g              2 0. 2 1 3 6  
A U C _ % E xtr a p _ pr e d                          %               3. 9 3 0 7  
V z _ F _ pr e d                                 L            2 1 7 5. 7 3 2 1  
Cl _ F _ pr e d                               L/ h              4 9. 4 7 1 5  
A U M Cl a st                          h* h* n g/ m L          5 2 9 2 3 8. 5 5 3 7  
A U M CI N F _ o b s                       h* h* n g/ m L          6 1 5 1 9 4. 2 8 0 7  
A U M C _ % E xtr a p _ o b s                          %              1 3. 9 7 2 1  
A U M CI N F _ pr e d                      h* h* n g/ m L          6 0 5 0 3 0. 6 9 8 2  
A U M C _ % E xtr a p _ pr e d                         %              1 2. 5 2 7 0  
M R Tl a st                                   h              6 0. 5 6 3 3  
M R TI N F _ o b s                                h              6 7. 2 7 7 8  
M R TI N F _ pr e d                               h              6 6. 5 1 5 1  
A U C 0 _ 2 4                             h* n g/ m L            1 2 2 9. 2 3 7 7  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 1  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:   Pl a s m a D at a,  E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 5 2 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 6 6 7       0. 0 0 0 0                          0. 0 6 9 3 3     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                          0. 0 6 9 3 3     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                          0. 0 6 9 3 3     0. 0 0 0 0  
      1. 0 0 0       0. 9 0 0 0                           0. 1 8 1 8     0. 1 1 2 5  
Pa ge 2 0 9 of 3 3 1
PI
PI


      1. 5 0 0        2. 8 1 0                            1. 1 0 9      1. 3 9 1  
      2. 0 0 0        6. 1 6 0                            3. 3 5 2      5. 5 2 5  
      3. 0 0 0        1 3. 5 0                            1 3. 1 8      3 1. 9 4  
      4. 0 0 0        2 3. 0 0                            3 1. 4 3      9 8. 1 9  
      6. 0 0 0        2 9. 9 0                            8 4. 3 3      3 6 9. 6  
      8. 0 0 0        6 0. 4 0                            1 7 4. 6      1 0 3 2.  
      1 2. 0 0        7 5. 3 0                            4 4 6. 0      3 8 0 6.  
      1 6. 0 0        9 8. 1 0                            7 9 2. 8      8 7 5 2.  
      2 4. 0 0        1 9 7. 0                            1 9 7 3. 3. 3 9 4 e + 0 0 4  
      3 6. 0 0        1 4 7. 0                            4 0 2 3. 9. 4 8 2 e + 0 0 4  
      4 8. 0 0        1 9 3. 0                            6 0 6 3. 1. 8 2 2 e + 0 0 5  
      6 0. 0 0        1 1 3. 0                            7 8 5 6. 2. 7 8 0 e + 0 0 5  
      7 2. 0 0 *      1 3 9. 0      1 3 3. 8      5. 2 4 9      9 3 6 8. 3. 7 8 8 e + 0 0 5      1. 0 0 0  
      9 6. 0 0 *      7 6. 2 0      8 1. 5 5     -5. 3 4 7 1. 1 8 8 e + 0 0 4 5. 8 6 4 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      5 3. 8 0      4 9. 7 2      4. 0 8 2 1. 3 4 2 e + 0 0 4 7. 5 2 1 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      2 7. 2 0      3 0. 3 1     -3. 1 1 3 1. 4 3 6 e + 0 0 4 8. 7 4 4 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      1 9. 6 0      1 8. 4 8      1. 1 1 9 1. 4 9 1 e + 0 0 4 9. 6 0 9 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 8 8 9  
R s q _ a dj u st e d                                              0. 9 8 5 2  
C orr _ X Y                                                  -0. 9 9 4 4  
N o _ p oi nt s _l a m b d a _ z                                        5  
L a m b d a _ z                                1/ h               0. 0 2 0 6  
L a m b d a _ z _l o w er                            h              7 2. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 3. 6 2 0 5  
Tl a g                                      h               0. 0 0 0 0  
T m a x                                      h              2 4. 0 0 0 0  
C m a x                                  n g/ m L             1 9 7. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 4 3 7 8  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L              1 9. 6 0 0 0  
A U Cl a st                             h* n g/ m L           1 4 9 1 2. 4 0 2 1  
A U C all                              h* n g/ m L           1 4 9 1 2. 4 0 2 1  
A U CI N F _ o b s                          h* n g/ m L           1 5 8 6 3. 0 8 2 9  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              3 5. 2 5 1 3  
A U C _ % E xtr a p _ o b s                           %               5. 9 9 3 0  
V z _ F _ o b s                                  L            1 3 7 5. 9 5 2 9  
Cl _ F _ o b s                                L/ h              2 8. 3 6 7 8  
A U CI N F _ pr e d                         h* n g/ m L           1 5 8 0 8. 8 2 5 8  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              3 5. 1 3 0 7  
A U C _ % E xtr a p _ pr e d                          %               5. 6 7 0 4  
V z _ F _ pr e d                                 L            1 3 8 0. 6 7 5 2  
Cl _ F _ pr e d                               L/ h              2 8. 4 6 5 1  
A U M Cl a st                          h* h* n g/ m L          9 6 0 8 7 7. 0 5 6 0  
A U M CI N F _ o b s                       h* h* n g/ m L         1 1 6 6 7 0 3. 3 5 8 5  
A U M C _ % E xtr a p _ o b s                          %              1 7. 6 4 1 7  
A U M CI N F _ pr e d                      h* h* n g/ m L         1 1 5 4 9 5 6. 4 8 2 6  
A U M C _ % E xtr a p _ pr e d                         %              1 6. 8 0 4 0  
M R Tl a st                                   h              6 4. 4 3 4 8  
M R TI N F _ o b s                                h              7 3. 5 4 8 3  
M R TI N F _ pr e d                               h              7 3. 0 5 7 7  
A U C 0 _ 2 4                             h* n g/ m L            1 9 7 3. 2 3 1 8  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 0  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
Pa ge 2 1 0 of 3 3 1
PI
PI


Settings 
-------- 
Model:  Plasma Data, Extravascular Administration 
Number of nonmissing observations:   22 
Dose time:      0.00 
Dose amount:      450.00 
Calculation method:  Linear Trapezoidal Rule for for Increasing Values, 
                     Log Trapezoidal Rule for Decreasing Values 
Weighting for lambda_z calculations:  Uniform weighting 
Lambda_z method:  Find best fit for lambda_z,  Log regression 
 
 
Summary Table 
------------- 
      Time         Conc.      Pred.    Residual      AUC       AUMC      Weight 
          h       ng/mL       ng/mL       ng/mL     h*ng/mL   h*h*ng/mL 
------------------------------------------------------------------------------- 
     0.0000       0.0000                           0.0000     0.0000 
     0.2500       0.0000                           0.0000     0.0000 
     0.5000       0.0000                           0.0000     0.0000 
     0.7500       0.5660                          0.07075    0.05306 
      1.000       0.6730                           0.2256     0.1903 
      1.500        1.690                           0.8164     0.9923 
      2.000        3.330                            2.071      3.291 
      3.000        7.990                            7.731      18.61 
      4.000        12.40                            17.93      55.39 
      6.017        20.00                            50.60      226.7 
      8.000        30.30                            100.5      586.5 
      12.00        47.10                            255.3      2202. 
      16.10        68.90                            493.1      5634. 
      24.07        101.0                            1170. 1.974e+004 
      36.00        92.30                            2322. 5.425e+004 
      48.00        107.0                            3518. 1.050e+005 
      60.02        83.60                            4658. 1.663e+005 
      72.00 *      82.30      89.60     -7.305      5652. 2.319e+005      1.000 
      96.17 *      59.60      56.25      3.347      7352. 3.737e+005      1.000 
      120.0 *      35.60      35.54    0.05729      8462. 4.925e+005      1.000 
      146.9 *      25.50      21.16      4.345      9277. 6.007e+005      1.000 
      168.0 *      12.00      14.10     -2.098      9654. 6.596e+005      1.000 
 
 
*) Starred values were included in the estimation of Lambda_z. 
 
 
Final Parameters 
--------------- 
Rsq                                                       0.9684 
Rsq_adjusted                                              0.9579 
Corr_XY                                                  -0.9841 
No_points_lambda_z                                        5 
Lambda_z                                1/h               0.0193 
Lambda_z_lower                            h              72.0000 
Lambda_z_upper                            h             168.0000 
HL_Lambda_z                               h              35.9813 
Tlag                                      h               0.5000 
Tmax                                      h              48.0000 
Cmax                                  ng/mL             107.0000 
Cmax_D                             ng/mL/mg               0.2378 
Tlast                                     h             168.0000 
Clast                                 ng/mL              12.0000 
AUClast                             h*ng/mL            9654.1066 
AUCall                              h*ng/mL            9654.1066 
AUCINF_obs                          h*ng/mL           10277.0279 
AUCINF_D_obs                     h*ng/mL/mg              22.8378 
AUC_%Extrap_obs                           %               6.0613 
Vz_F_obs                                  L            2272.9865 
Cl_F_obs                                L/h              43.7870 
AUCINF_pred                         h*ng/mL           10385.9548 
AUCINF_D_pred                    h*ng/mL/mg              23.0799 
AUC_%Extrap_pred                          %               7.0465 
Vz_F_pred                                 L            2249.1476 
Cl_F_pred                               L/h              43.3277 
AUMClast                          h*h*ng/mL          659645.6195 
Page 211 of 331


A U M CI N F _ o b s                       h* h* n g/ m L          7 9 6 6 3 2. 2 8 5 1  
A U M C _ % E xtr a p _ o b s                          %              1 7. 1 9 5 7  
A U M CI N F _ pr e d                      h* h* n g/ m L          8 2 0 5 8 6. 4 2 3 0  
A U M C _ % E xtr a p _ pr e d                         %              1 9. 6 1 2 9  
M R Tl a st                                   h              6 8. 3 2 8 0  
M R TI N F _ o b s                                h              7 7. 5 1 5 8  
M R TI N F _ pr e d                               h              7 9. 0 0 9 2  
A U C 0 _ 2 4                             h* n g/ m L            1 1 6 3. 1 2 1 2  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 1  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 8 6 9 0                           0. 1 0 8 6     0. 1 0 8 6  
      1. 5 0 0        1. 8 9 0                           0. 7 9 8 4      1. 0 3 5  
      2. 0 0 0        3. 1 6 0                            2. 0 6 1      3. 3 2 3  
      3. 0 0 0        8. 6 5 0                            7. 9 6 6      1 9. 4 6  
      4. 0 0 0        1 8. 5 0                            2 1. 5 4      6 9. 4 3  
      6. 0 0 0        2 7. 8 0                            6 7. 8 4      3 1 0. 2  
      8. 0 0 0        3 8. 9 0                            1 3 4. 5      7 8 8. 2  
      1 2. 0 0        5 0. 9 0                            3 1 4. 1      2 6 3 2.  
      1 6. 0 0        6 2. 2 0                            5 4 0. 3      5 8 4 4.  
      2 4. 0 2        8 0. 7 0                            1 1 1 3. 1. 7 6 0 e + 0 0 4  
      3 6. 0 0        7 8. 3 0                            2 0 6 6. 4. 6 1 6 e + 0 0 4  
      4 8. 0 0        1 0 2. 0                            3 1 4 8. 9. 2 4 5 e + 0 0 4  
      6 0. 0 0        6 7. 0 0                            4 1 4 7. 1. 4 6 0 e + 0 0 5  
      7 2. 0 0        6 6. 0 0                            4 9 4 5. 1. 9 8 6 e + 0 0 5  
      9 6. 0 0 *      5 8. 0 0      5 7. 9 8    0. 0 1 5 4 3      6 4 3 1. 3. 2 3 1 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      4 0. 1 0      3 8. 0 6      2. 0 4 0      7 5 9 6. 4. 4 8 0 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      2 2. 5 0      2 5. 0 0     -2. 4 9 6      8 3 2 6. 5. 4 3 6 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      1 7. 3 0      1 6. 4 1     0. 8 8 8 4      8 8 0 1. 6. 1 7 5 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 8 1 6  
R s q _ a dj u st e d                                              0. 9 7 2 4  
C orr _ X Y                                                  -0. 9 9 0 8  
N o _ p oi nt s _l a m b d a _ z                                        4  
L a m b d a _ z                                1/ h               0. 0 1 7 5 
Pa ge 2 1 2 of 3 3 1
PI
PI


L a m b d a _ z _l o w er                            h              9 6. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              3 9. 5 3 9 8  
Tl a g                                      h               0. 7 5 0 0  
T m a x                                      h              4 8. 0 0 0 0  
C m a x                                  n g/ m L             1 0 2. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 2 2 6 7  
Tl a st                                      h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L              1 7. 3 0 0 0  
A U Cl a st                             h* n g/ m L            8 8 0 0. 9 4 5 4  
A U C all                              h* n g/ m L            8 8 0 0. 9 4 5 4  
A U CI N F _ o b s                          h* n g/ m L            9 7 8 7. 8 0 3 9  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              2 1. 7 5 0 7  
A U C _ % E xtr a p _ o b s                           %              1 0. 0 8 2 5  
V z _ F _ o b s                                  L            2 6 2 2. 6 2 4 0  
Cl _ F _ o b s                                L/ h              4 5. 9 7 5 6  
A U CI N F _ pr e d                         h* n g/ m L            9 7 3 7. 1 2 7 4  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              2 1. 6 3 8 1  
A U C _ % E xtr a p _ pr e d                          %               9. 6 1 4 6  
V z _ F _ pr e d                                 L            2 6 3 6. 2 7 3 3  
Cl _ F _ pr e d                               L/ h              4 6. 2 1 4 9  
A U M Cl a st                          h* h* n g/ m L          6 1 7 4 5 4. 0 7 9 3  
A U M CI N F _ o b s                       h* h* n g/ m L          8 3 9 5 4 0. 5 0 3 4  
A U M C _ % E xtr a p _ o b s                          %              2 6. 4 5 3 3  
A U M CI N F _ pr e d                      h* h* n g/ m L          8 2 8 1 3 6. 0 8 3 0  
A U M C _ % E xtr a p _ pr e d                         %              2 5. 4 4 0 5  
M R Tl a st                                   h              7 0. 1 5 7 7  
M R TI N F _ o b s                                h              8 5. 7 7 4 1  
M R TI N F _ pr e d                               h              8 5. 0 4 9 3  
A U C 0 _ 2 4                             h* n g/ m L            1 1 1 1. 7 8 7 0  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D =
, A P E RI O D = 1, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3 
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 3  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 5 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0        1. 3 5 0                           0. 3 0 3 8     0. 4 5 5 6  
      2. 0 0 0        3. 3 5 0                            1. 4 7 9      2. 6 3 7  
      3. 0 0 0        6. 8 9 0                            6. 5 9 9      1 6. 3 2  
      4. 0 0 0        1 4. 4 0                            1 7. 2 4      5 5. 4 6  
      6. 0 0 0        1 8. 6 0                            5 0. 2 4      2 2 4. 7  
      8. 0 1 7        3 1. 7 0                            1 0 1. 0      5 9 3. 4  
      1 2. 0 0        5 5. 7 0                            2 7 5. 0      2 4 3 1.  
Pa ge 2 1 3 of 3 3 1
PI
PI


      1 6. 0 3        7 2. 1 0                            5 3 2. 8      6 1 1 0.  
      2 4. 0 0        1 5 4. 0                            1 4 3 3. 2. 5 4 4 e + 0 0 4  
      3 6. 0 7        1 1 5. 0                            3 0 4 5. 7. 3 3 6 e + 0 0 4  
      4 8. 0 0        1 4 8. 0                            4 6 1 4. 1. 4 0 5 e + 0 0 5  
      6 0. 0 0        8 7. 6 0                            5 9 9 6. 2. 1 4 4 e + 0 0 5  
      7 2. 0 0 *      1 1 2. 0      1 1 1. 5     0. 4 9 1 8      7 1 9 4. 2. 9 4 3 e + 0 0 5      1. 0 0 0  
      9 6. 0 0 *      6 4. 5 0      6 3. 5 9     0. 9 0 5 0      9 2 6 0. 4. 6 5 6 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      3 5. 1 0      3 6. 2 7     -1. 1 6 9 1. 0 4 2 e + 0 0 4 5. 8 9 4 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      2 0. 8 0      2 0. 6 8     0. 1 1 5 0 1. 1 0 8 e + 0 0 4 6. 7 5 3 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      1 1. 9 0      1 1. 8 0     0. 1 0 3 0 1. 1 4 6 e + 0 0 4 7. 3 4 6 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 9 6  
R s q _ a dj u st e d                                              0. 9 9 9 4  
C orr _ X Y                                                  -0. 9 9 9 8  
N o _ p oi nt s _l a m b d a _ z                                        5  
L a m b d a _ z                                1/ h               0. 0 2 3 4  
L a m b d a _ z _l o w er                            h              7 2. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              2 9. 6 2 3 6  
Tl a g                                      h               1. 0 5 0 0  
T m a x                                      h              2 4. 0 0 0 0  
C m a x                                  n g/ m L             1 5 4. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 3 4 2 2  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                  n g/ m L              1 1. 9 0 0 0  
A U Cl a st                             h* n g/ m L           1 1 4 5 7. 7 2 4 6  
A U C all                              h* n g/ m L           1 1 4 5 7. 7 2 4 6  
A U CI N F _ o b s                          h* n g/ m L           1 1 9 6 6. 3 0 4 8  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              2 6. 5 9 1 8  
A U C _ % E xtr a p _ o b s                           %               4. 2 5 0 1  
V z _ F _ o b s                                  L            1 6 0 7. 1 8 1 6  
Cl _ F _ o b s                                L/ h              3 7. 6 0 5 6  
A U CI N F _ pr e d                         h* n g/ m L           1 1 9 6 1. 9 0 2 5  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              2 6. 5 8 2 0  
A U C _ % E xtr a p _ pr e d                          %               4. 2 1 4 9  
V z _ F _ pr e d                                 L            1 6 0 7. 7 7 3 1  
Cl _ F _ pr e d                               L/ h              3 7. 6 1 9 4  
A U M Cl a st                          h* h* n g/ m L          7 3 4 5 7 2. 8 3 0 6  
A U M CI N F _ o b s                       h* h* n g/ m L          8 4 1 7 4 9. 9 2 6 3  
A U M C _ % E xtr a p _ o b s                          %              1 2. 7 3 2 7  
A U M CI N F _ pr e d                      h* h* n g/ m L          8 4 0 8 2 2. 1 9 7 9  
A U M C _ % E xtr a p _ pr e d                         %              1 2. 6 3 6 4  
M R Tl a st                                   h              6 4. 1 1 1 6  
M R TI N F _ o b s                                h              7 0. 3 4 3 3  
M R TI N F _ pr e d                               h              7 0. 2 9 1 7  
A U C 0 _ 2 4                             h* n g/ m L            1 4 3 3. 3 9 6 3  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 0  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
Pa ge 2 1 4 of 3 3 1
PI
PI


                     Log Trapezoidal Rule for Decreasing Values 
Weighting for lambda_z calculations:  Uniform weighting 
Lambda_z method:  Find best fit for lambda_z,  Log regression 
 
 
Summary Table 
------------- 
      Time         Conc.      Pred.    Residual      AUC       AUMC      Weight 
          h       ng/mL       ng/mL       ng/mL     h*ng/mL   h*h*ng/mL 
------------------------------------------------------------------------------- 
     0.0000       0.0000                           0.0000     0.0000 
     0.2500       0.0000                           0.0000     0.0000 
     0.5000       0.0000                           0.0000     0.0000 
     0.7500        1.000                           0.1250    0.09375 
      1.000        2.050                           0.5063     0.4438 
      1.500        5.360                            2.359      2.966 
      2.000        8.750                            5.886      9.351 
      3.000        15.70                            18.11      41.65 
      4.000        20.80                            36.36      106.8 
      6.000        26.80                            83.96      350.8 
      8.000        37.10                            147.9      808.4 
      12.00        52.20                            326.5      2655. 
      16.00        89.70                            610.3      6778. 
      24.00        103.0                            1381. 2.241e+004 
      36.00        102.0                            2611. 5.929e+004 
      48.00        150.0                            4123. 1.245e+005 
      60.00        98.30                            5591. 2.032e+005 
      72.02        118.0                            6891. 2.897e+005 
      96.00        85.30                            9307. 4.911e+005 
      120.0 *      93.90      91.06      2.836 1.146e+004 7.246e+005      1.000 
      144.1 *      44.10      46.90     -2.797 1.304e+004 9.316e+005      1.000 
      168.0 *      25.00      24.24     0.7592 1.385e+004 1.056e+006      1.000 
 
 
*) Starred values were included in the estimation of Lambda_z. 
 
 
Final Parameters 
--------------- 
Rsq                                                       0.9936 
Rsq_adjusted                                              0.9871 
Corr_XY                                                  -0.9968 
No_points_lambda_z                                        3 
Lambda_z                                1/h               0.0276 
Lambda_z_lower                            h             120.0000 
Lambda_z_upper                            h             168.0000 
HL_Lambda_z                               h              25.1382 
Tlag                                      h               0.5000 
Tmax                                      h              48.0000 
Cmax                                  ng/mL             150.0000 
Cmax_D                             ng/mL/mg               0.3333 
Tlast                                     h             168.0000 
Clast                                 ng/mL              25.0000 
AUClast                             h*ng/mL           13849.0200 
AUCall                              h*ng/mL           13849.0200 
AUCINF_obs                          h*ng/mL           14755.6894 
AUCINF_D_obs                     h*ng/mL/mg              32.7904 
AUC_%Extrap_obs                           %               6.1445 
Vz_F_obs                                  L            1106.0174 
Cl_F_obs                                L/h              30.4967 
AUCINF_pred                         h*ng/mL           14728.1570 
AUCINF_D_pred                    h*ng/mL/mg              32.7292 
AUC_%Extrap_pred                          %               5.9691 
Vz_F_pred                                 L            1108.0850 
Cl_F_pred                               L/h              30.5537 
AUMClast                          h*h*ng/mL         1056380.8901 
AUMCINF_obs                       h*h*ng/mL         1241583.3282 
AUMC_%Extrap_obs                          %              14.9166 
AUMCINF_pred                      h*h*ng/mL         1235959.3775 
AUMC_%Extrap_pred                         %              14.5295 
MRTlast                                   h              76.2784 
MRTINF_obs                                h              84.1427 
MRTINF_pred                               h              83.9181 
Page 215 of 331


A U C 0 _ 2 4                             h* n g/ m L            1 3 8 1. 0 6 1 3  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 1  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:   Pl a s m a D at a,  E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 6 1 2 0                          0. 0 7 6 5 0    0. 0 7 6 5 0  
      1. 5 0 0        1. 5 3 0                           0. 6 1 2 0     0. 8 0 3 3  
      2. 0 0 0        4. 1 2 0                            2. 0 2 5      3. 4 3 7  
      3. 0 0 0        8. 8 2 0                            8. 4 9 5      2 0. 7 9  
      4. 0 0 0        1 7. 2 0                            2 1. 5 0      6 8. 4 2  
      6. 0 0 0         2 2. 9 0                            6 1. 6 0      2 7 4. 6  
      8. 0 0 0        3 4. 0 0                            1 1 8. 5      6 8 4. 0  
      1 2. 0 0        5 9. 6 0                            3 0 5. 7      2 6 5 8.  
      1 6. 0 0        7 9. 7 0                            5 8 4. 3      6 6 3 9.  
      2 4. 0 0        1 1 7. 0                            1 3 7 1. 2. 2 9 7 e + 0 0 4  
      3 6. 0 3        1 1 8. 0                            2 7 8 5. 6. 5 4 5 e + 0 0 4  
      4 8. 0 0        1 1 8. 0                            4 1 9 7. 1. 2 4 8 e + 0 0 5  
      6 0. 0 0        8 0. 8 0                            5 3 7 6. 1. 8 8 0 e + 0 0 5  
      7 2. 0 0 *      7 9. 0 0      8 3. 5 5     -4. 5 5 3      6 3 3 5. 2. 5 1 2 e + 0 0 5      1. 0 0 0  
      9 6. 0 0 *      5 1. 0 0      4 4. 1 3      6. 8 7 0      7 8 7 0. 3. 7 8 9 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      2 2. 1 0      2 3. 3 1     -1. 2 0 8      8 7 0 0. 4. 6 7 1 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      1 1. 1 0      1 2. 3 1     -1. 2 1 1      9 0 8 3. 5. 1 7 2 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      6. 9 6 0      6. 5 0 2     0. 4 5 8 0      9 2 9 6. 5. 5 0 2 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 8 9 7  
R s q _ a dj u st e d                                              0. 9 8 6 3  
C orr _ X Y                                                  -0. 9 9 4 9  
N o _ p oi nt s _l a m b d a _ z                                        5  
L a m b d a _ z                                1/ h               0. 0 2 6 6  
L a m b d a _ z _l o w er                            h              7 2. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              2 6. 0 6 0 5  
Tl a g                                      h               0. 7 5 0 0  
T m a x                                      h              3 6. 0 3 3 3  
C m a x                                  n g/ m L             1 1 8. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 2 6 2 2  
Pa ge 2 1 6 of 3 3 1
PI
PI


Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L               6. 9 6 0 0  
A U Cl a st                             h* n g/ m L            9 2 9 5. 8 2 0 6  
A U C all                              h* n g/ m L            9 2 9 5. 8 2 0 6  
A U CI N F _ o b s                          h* n g/ m L            9 5 5 7. 4 9 8 6  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              2 1. 2 3 8 9  
A U C _ % E xtr a p _ o b s                           %               2. 7 3 7 9  
V z _ F _ o b s                                  L            1 7 7 0. 2 1 6 1  
Cl _ F _ o b s                                L/ h              4 7. 0 8 3 4  
A U CI N F _ pr e d                         h* n g/ m L            9 5 4 0. 2 7 9 4  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              2 1. 2 0 0 6  
A U C _ % E xtr a p _ pr e d                          %               2. 5 6 2 4  
V z _ F _ pr e d                                 L            1 7 7 3. 4 1 1 1  
Cl _ F _ pr e d                               L/ h              4 7. 1 6 8 4  
A U M Cl a st                          h* h* n g/ m L          5 5 0 1 8 7. 6 1 1 2  
A U M CI N F _ o b s                       h* h* n g/ m L          6 0 3 9 8 7. 9 3 6 4  
A U M C _ % E xtr a p _ o b s                          %               8. 9 0 7 5  
A U M CI N F _ pr e d                      h* h* n g/ m L          6 0 0 4 4 7. 7 2 1 0  
A U M C _ % E xtr a p _ pr e d                         %               8. 3 7 0 4  
M R Tl a st                                   h              5 9. 1 8 6 6  
M R TI N F _ o b s                                h              6 3. 1 9 5 2  
M R TI N F _ pr e d                               h              6 2. 9 3 8 2  
A U C 0 _ 2 4                             h* n g/ m L            1 3 7 1. 1 0 4 5  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 2, T R T A = 2 x 2 5 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 2  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:   Pl a s m a D at a,  E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 5 0 7 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 5 3 5 0                           0. 1 3 0 3    0. 0 1 6 7 2  
     0. 5 0 0 0       0. 5 1 4 0                           0. 2 6 1 4    0. 0 6 5 7 7  
     0. 7 5 0 0       0. 6 7 3 0                           0. 4 0 9 7     0. 1 6 1 0  
      1. 0 0 0        1. 1 1 0                           0. 6 3 2 6     0. 3 6 2 8  
      1. 5 0 0        2. 0 0 0                            1. 4 1 0      1. 3 9 0  
      2. 0 0 0        3. 4 7 0                            2. 7 7 8      3. 8 7 5  
      3. 0 0 0        7. 3 1 0                            8. 1 6 8      1 8. 3 1  
      4. 0 0 0        1 1. 0 0                            1 7. 3 2      5 1. 2 8  
      6. 0 0 0        2 0. 6 0                            4 8. 9 2      2 1 8. 9  
      8. 0 0 0        3 1. 1 0                            1 0 0. 6      5 9 1. 3  
      1 2. 0 0        4 8. 9 0                            2 6 0. 6      2 2 6 2.  
      1 6. 0 0        7 1. 9 0                            5 0 2. 2      5 7 3 7.  
      2 4. 0 2        1 0 4. 0                            1 2 0 7. 2. 0 3 6 e + 0 0 4  
      3 6. 0 0        9 6. 6 0                            2 4 0 9. 5. 6 3 2 e + 0 0 4  
      4 8. 0 0        1 2 4. 0                            3 7 3 2. 1. 1 2 9 e + 0 0 5  
      6 0. 0 0        1 1 2. 0                            5 1 4 7. 1. 8 9 2 e + 0 0 5  
      7 2. 0 0        1 2 2. 0                            6 5 5 1. 2. 8 2 2 e + 0 0 5  
      9 6. 0 0        9 0. 6 0                            9 0 8 4. 4. 9 3 4 e + 0 0 5  
Pa ge 2 1 7 of 3 3 1
PI
PI


      1 2 0. 0 *      5 7. 6 0      5 7. 1 4     0. 4 6 2 6 1. 0 8 3 e + 0 0 4 6. 8 0 7 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      4 6. 5 0      4 7. 2 6    -0. 7 5 6 0 1. 2 0 8 e + 0 0 4 8. 4 4 4 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      3 9. 4 0      3 9. 0 8     0. 3 1 6 4 1. 3 1 1 e + 0 0 4 1. 0 0 5 e + 0 0 6      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 4 6  
R s q _ a dj u st e d                                              0. 9 8 9 2  
C orr _ X Y                                                  -0. 9 9 7 3  
N o _ p oi nt s _l a m b d a _ z                                        3 
L a m b d a _ z                                1/ h               0. 0 0 7 9  
L a m b d a _ z _l o w er                            h             1 2 0. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              8 7. 6 1 1 5  
Tl a g                                      h               0. 0 0 0 0  
T m a x                                      h              4 8. 0 0 0 0  
C m a x                                  n g/ m L             1 2 4. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 2 7 5 6  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L              3 9. 4 0 0 0  
A U Cl a st                             h* n g/ m L           1 3 1 0 5. 0 9 8 3  
A U C all                              h* n g/ m L           1 3 1 0 5. 0 9 8 3  
A U CI N F _ o b s                          h* n g/ m L           1 8 0 8 5. 1 2 8 3  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              4 0. 1 8 9 2  
A U C _ % E xtr a p _ o b s                           %              2 7. 5 3 6 6  
V z _ F _ o b s                                  L            3 1 4 5. 0 4 3 5  
Cl _ F _ o b s                                L/ h              2 4. 8 8 2 3  
A U CI N F _ pr e d                         h* n g/ m L           1 8 0 4 5. 1 3 1 0  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              4 0. 1 0 0 3  
A U C _ % E xtr a p _ pr e d                          %              2 7. 3 7 6 0  
V z _ F _ pr e d                                 L            3 1 5 2. 0 1 4 5  
Cl _ F _ pr e d                               L/ h              2 4. 9 3 7 5  
A U M Cl a st                          h* h* n g/ m L         1 0 0 4 5 1 0. 3 9 7 9  
A U M CI N F _ o b s                       h* h* n g/ m L         2 4 7 0 6 1 4. 7 8 2 0  
A U M C _ % E xtr a p _ o b s                          %              5 9. 3 4 1 7  
A U M CI N F _ pr e d                      h* h* n g/ m L         2 4 5 8 8 3 9. 7 1 5 9  
A U M C _ % E xtr a p _ pr e d                         %              5 9. 1 4 7 0  
M R Tl a st                                   h              7 6. 6 5 0 4  
M R TI N F _ o b s                                h             1 3 6. 6 1 0 3  
M R TI N F _ pr e d                               h             1 3 6. 2 6 0 6  
A U C 0 _ 2 4                             h* n g/ m L            1 2 0 5. 5 5 5 7  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 1  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m  w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
Pa ge 2 1 8 of 3 3 1
PI
PI


      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 8 3 3       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0       0. 7 0 5 0                           0. 1 7 6 3     0. 2 6 4 4  
      2. 0 0 0        1. 7 7 0                           0. 7 9 5 0      1. 4 1 4  
      3. 0 0 0        6. 2 4 0                            4. 8 0 0      1 2. 5 4  
      4. 0 0 0        1 2. 4 0                            1 4. 1 2      4 6. 7 0  
      6. 0 0 0        2 5. 2 0                            5 1. 7 2      2 4 7. 5  
      8. 0 0 0        3 5. 4 0                            1 1 2. 3      6 8 1. 9  
      1 2. 0 0        5 3. 0 0                            2 8 9. 1      2 5 2 0.  
      1 6. 0 0        6 3. 9 0                            5 2 2. 9      5 8 3 7.  
      2 4. 0 0        1 0 0. 0                            1 1 7 9. 1. 9 5 3 e + 0 0 4  
      3 6. 0 0        9 1. 6 0                            2 3 2 7. 5. 3 8 9 e + 0 0 4  
      4 8. 0 0        1 1 2. 0                            3 5 4 9. 1. 0 5 9 e + 0 0 5  
      6 0. 0 0        1 0 0. 0                            4 8 2 0. 1. 7 4 4 e + 0 0 5  
      7 2. 0 0 *      1 0 9. 0      1 1 4. 6     -5. 6 0 0      6 0 7 4. 2. 5 7 5 e + 0 0 5      1. 0 0 0  
      9 6. 0 0 *      8 4. 2 0      7 9. 7 5      4. 4 5 0      8 3 7 9. 4. 5 0 0 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      5 2. 1 0      5 5. 5 0     -3. 3 9 8      9 9 8 4. 6. 2 1 8 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      4 5. 5 0      3 8. 6 2      6. 8 7 9 1. 1 1 5 e + 0 0 4 7. 7 5 8 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      2 4. 2 0      2 6. 8 8     -2. 6 7 7 1. 1 9 6 e + 0 0 4 9. 0 1 1 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 6 5 2  
R s q _ a dj u st e d                                              0. 9 5 3 7  
C orr _ X Y                                                  -0. 9 8 2 5  
N o _ p oi nt s _l a m b d a _ z                                        5 
L a m b d a _ z                                1/ h               0. 0 1 5 1  
L a m b d a _ z _l o w er                            h              7 2. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              4 5. 8 8 5 1  
Tl a g                                      h               1. 0 0 0 0  
T m a x                                      h              4 8. 0 0 0 0  
C m a x                                  n g/ m L             1 1 2. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 2 4 8 9  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                 n g/ m L              2 4. 2 0 0 0  
A U Cl a st                             h* n g/ m L           1 1 9 6 3. 2 2 6 7  
A U C all                              h* n g/ m L           1 1 9 6 3. 2 2 6 7  
A U CI N F _ o b s                          h* n g/ m L           1 3 5 6 5. 2 2 4 5  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              3 0. 1 4 4 9  
A U C _ % E xtr a p _ o b s                           %              1 1. 8 0 9 6  
V z _ F _ o b s                                  L            2 1 9 5. 9 9 8 7  
Cl _ F _ o b s                                L/ h              3 3. 1 7 3 1  
A U CI N F _ pr e d                         h* n g/ m L           1 3 7 4 2. 4 1 7 7  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              3 0. 5 3 8 7  
A U C _ % E xtr a p _ pr e d                          %              1 2. 9 4 6 7  
V z _ F _ pr e d                                 L            2 1 6 7. 6 8 3 8  
Cl _ F _ pr e d                               L/ h              3 2. 7 4 5 3  
A U M Cl a st                          h* h* n g/ m L          9 0 1 1 0 8. 7 5 9 1  
A U M CI N F _ o b s                       h* h * n g/ m L         1 2 7 6 2 9 3. 8 5 6 9 
A U M C _ % E xtr a p _ o b s                          %              2 9. 3 9 6 5  
A U M CI N F _ pr e d                      h* h* n g/ m L         1 3 1 7 7 9 2. 1 9 5 8  
A U M C _ % E xtr a p _ pr e d                         %              3 1. 6 1 9 8  
M R Tl a st                                    h              7 5. 3 2 3 2  
M R TI N F _ o b s                                h              9 4. 0 8 5 7  
M R TI N F _ pr e d                               h              9 5. 8 9 2 3  
A U C 0 _ 2 4                             h* n g/ m L            1 1 7 8. 5 2 0 0  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
Pa ge 2 1 9 of 3 3 1
PI


                                                  Date:    
 
                                                  Time:     09:24:10 
 
 
                  WINNONLIN NONCOMPARTMENTAL ANALYSIS PROGRAM 
                                   7.0.0.2535 
                            Core Version 04Jun2007 
 
Settings 
-------- 
Model:  Plasma Data, Extravascular Administration 
Number of nonmissing observations:   22 
Dose time:      0.00 
Dose amount:      450.00 
Calculation method:  Linear Trapezoidal Rule for for Increasing Values, 
                     Log Trapezoidal Rule for Decreasing Values 
Weighting for lambda_z calculations:  Uniform weighting 
Lambda_z method:  Find best fit for lambda_z,  Log regression 
 
 
Summary Table 
------------- 
      Time         Conc.      Pred.    Residual      AUC       AUMC      Weight 
          h       ng/mL       ng/mL       ng/mL     h*ng/mL   h*h*ng/mL 
------------------------------------------------------------------------------- 
     0.0000       0.0000                           0.0000     0.0000 
     0.2500       0.0000                           0.0000     0.0000 
     0.5000       0.0000                           0.0000     0.0000 
     0.7500       0.0000                           0.0000     0.0000 
      1.000       0.7770                          0.09713    0.09713 
      1.500        3.990                            1.289      1.788 
      2.000        8.210                            4.339      7.389 
      3.000        17.00                            16.94      41.10 
      4.000        31.00                            40.94      128.6 
      6.000        36.70                            108.6      472.8 
      8.000        51.80                            197.1      1107. 
      12.00        58.90                            418.5      3350. 
      16.00        95.40                            727.1      7816. 
      24.02        102.0                            1518. 2.375e+004 
      36.00        83.80                            2628. 5.684e+004 
      48.00        86.40                            3649. 9.982e+004 
      60.00        60.70                            4523. 1.467e+005 
      72.02        65.60                            5282. 1.970e+005 
      96.00        62.10                            6813. 3.254e+005 
      120.3 *      57.50      57.89    -0.3949      8264. 4.821e+005      1.000 
      144.0 *      33.20      32.75     0.4470      9312. 6.194e+005      1.000 
      168.1 *      18.20      18.32    -0.1226      9914. 7.128e+005      1.000 
 
 
*) Starred values were included in the estimation of Lambda_z. 
 
 
Final Parameters 
--------------- 
Rsq                                                       0.9996 
Rsq_adjusted                                              0.9992 
Corr_XY                                                  -0.9998 
No_points_lambda_z                                        3 
Lambda_z                                1/h               0.0241 
Lambda_z_lower                            h             120.2833 
Lambda_z_upper                            h             168.1167 
HL_Lambda_z                               h              28.8185 
Tlag                                      h               0.7500 
Tmax                                      h              24.0167 
Cmax                                  ng/mL             102.0000 
Cmax_D                             ng/mL/mg               0.2267 
Tlast                                     h             168.1167 
Clast                                 ng/mL              18.2000 
AUClast                             h*ng/mL            9914.4950 
AUCall                              h*ng/mL            9914.4950 
AUCINF_obs                          h*ng/mL           10671.1834 
AUCINF_D_obs                     h*ng/mL/mg              23.7137 
AUC_%Extrap_obs                           %               7.0910 
Page 220 of 331
PI


V z _ F _ o b s                                  L            1 7 5 3. 2 5 7 1  
Cl _ F _ o b s                                 L/ h              4 2. 1 6 9 6  
A U CI N F _ pr e d                         h* n g/ m L           1 0 6 7 6. 2 7 9 4  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              2 3. 7 2 5 1  
A U C _ % E xtr a p _ pr e d                          %               7. 1 3 5 3  
V z _ F _ pr e d                                 L            1 7 5 2. 4 2 0 3  
Cl _ F _ pr e d                               L/ h              4 2. 1 4 9 5  
A U M Cl a st                          h* h* n g/ m L          7 1 2 7 5 2. 7 1 2 8  
A U M CI N F _ o b s                       h* h* n g/ m L          8 7 1 4 2 4. 9 3 4 0  
A U M C _ % E xtr a p _ o b s                          %              1 8. 2 0 8 4  
A U M CI N F _ pr e d                      h* h* n g/ m L          8 7 2 4 9 3. 5 2 6 6  
A U M C _ % E xtr a p _ pr e d                         %              1 8. 3 0 8 5  
M R Tl a st                                   h              7 1. 8 9 0 0  
M R TI N F _ o b s                                h              8 1. 6 6 1 5  
M R TI N F _ pr e d                               h              8 1. 7 2 2 6  
A U C 0 _ 2 4                             h* n g/ m L            1 5 1 6. 6 8 9 0  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 1, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 1  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
      1. 5 0 0        1. 5 2 0                           0. 3 8 0 0     0. 5 7 0 0  
      2. 0 0 0        2. 4 1 0                            1. 3 6 3      2. 3 4 5  
      3. 0 0 0        6. 0 1 0                            5. 5 7 3      1 3. 7 7  
      4. 0 0 0        8. 6 8 0                            1 2. 9 2      4 0. 1 5  
      6. 0 0 0        1 3. 5 0                            3 5. 1 0      1 5 5. 9  
      8. 0 0 0        1 8. 5 0                            6 7. 1 0      3 8 4. 9  
      1 2. 0 0        3 4. 2 0                            1 7 2. 5      1 5 0 2.  
      1 6. 0 0        4 4. 7 0                            3 3 0. 3      3 7 5 3.  
      2 4. 0 0        6 9. 5 0                            7 8 7. 1 1. 3 2 9 e + 0 0 4  
      3 6. 0 0        9 3. 6 0                            1 7 6 6. 4. 3 5 1 e + 0 0 4  
      4 8. 0 0        1 0 7. 0                            2 9 6 9. 9. 4 5 4 e + 0 0 4  
      6 0. 0 3        6 5. 4 0                            3 9 8 6. 1. 4 9 0 e + 0 0 5  
      7 2. 0 0 *      5 6. 9 0      5 6. 0 2     0. 8 7 5 4      4 7 1 7. 1. 9 7 1 e + 0 0 5      1. 0 0 0  
      9 6. 0 0 *      2 9. 6 0      3 1. 7 0     -2. 0 9 6      5 7 1 9. 2. 8 0 0 e + 0 0 5      1. 0 0 0  
      1 2 0. 0 *      1 8. 5 0      1 7. 9 3     0. 5 6 7 8      6 2 8 6. 3. 4 0 7 e + 0 0 5      1. 0 0 0  
      1 4 4. 0 *      1 1. 0 0      1 0. 1 5     0. 8 5 4 8      6 6 3 2. 3. 8 6 0 e + 0 0 5      1. 0 0 0  
      1 6 8. 0 *      5. 4 1 0      5. 7 4 0    -0. 3 2 9 7      6 8 2 1. 4. 1 5 3 e + 0 0 5      1. 0 0 0  
 
 
*) St arr e d v al u e s w er e i n cl u d e d i n t h e e sti m ati o n of L a m b d a _ z. 
 
Pa ge 2 2 1 of 3 3 1
PI
PI


 
Fi n al P ar a m et er s  
--------------- 
R s q                                                       0. 9 9 5 1  
R s q _ a dj u st e d                                              0. 9 9 3 5  
C orr _ X Y                                                  -0. 9 9 7 6  
N o _ p oi nt s _l a m b d a _ z                                        5  
L a m b d a _ z                                1/ h               0. 0 2 3 7  
L a m b d a _ z _l o w er                            h              7 2. 0 0 0 0  
L a m b d a _ z _ u p p er                            h             1 6 8. 0 0 0 0  
H L _ L a m b d a _ z                               h              2 9. 2 0 5 8  
Tl a g                                      h               1. 0 0 0 0  
T m a x                                      h              4 8. 0 0 0 0  
C m a x                                  n g/ m L             1 0 7. 0 0 0 0  
C m a x _ D                             n g/ m L/ m g               0. 2 3 7 8  
Tl a st                                     h             1 6 8. 0 0 0 0  
Cl a st                                  n g/ m L               5. 4 1 0 0  
A U Cl a st                             h* n g/ m L            6 8 2 1. 3 6 0 4  
A U C all                              h* n g/ m L            6 8 2 1. 3 6 0 4  
A U CI N F _ o b s                          h* n g/ m L            7 0 4 9. 3 1 1 0  
A U CI N F _ D _ o b s                     h* n g/ m L/ m g              1 5. 6 6 5 1  
A U C _ % E xtr a p _ o b s                           %               3. 2 3 3 7  
V z _ F _ o b s                                  L            2 6 8 9. 7 3 3 6  
Cl _ F _ o b s                                L/ h              6 3. 8 3 6 0  
A U CI N F _ pr e d                         h* n g/ m L            7 0 6 3. 2 0 1 9  
A U CI N F _ D _ pr e d                    h* n g/ m L/ m g              1 5. 6 9 6 0  
A U C _ % E xtr a p _ pr e d                          %               3. 4 2 4 0  
V z _ F _ pr e d                                 L            2 6 8 4. 4 4 3 8  
Cl _ F _ pr e d                               L/ h              6 3. 7 1 0 5  
A U M Cl a st                          h* h* n g/ m L          4 1 5 2 6 8. 7 7 5 7  
A U M CI N F _ o b s                       h* h* n g/ m L          4 6 3 1 6 9. 1 7 9 3  
A U M C _ % E xtr a p _ o b s                          %              1 0. 3 4 1 9  
A U M CI N F _ pr e d                      h* h* n g/ m L          4 6 6 0 8 8. 1 4 0 6  
A U M C _ % E xtr a p _ pr e d                         %              1 0. 9 0 3 4  
M R Tl a st                                   h              6 0. 8 7 7 7  
M R TI N F _ o b s                                h              6 5. 7 0 4 2  
M R TI N F _ pr e d                               h              6 5. 9 8 8 2  
A U C 0 _ 2 4                             h* n g/ m L             7 8 7. 0 9 7 5  
 
 
 
Wi n N o nli n 7. 0. 0. 2 5 3 5  
P A R A M C D = M 9 A, S U B JI D = 
, A P E RI O D = 2, T R T A N = 1, T R T A = 5 x 1 0 0 m g T F 3  
 
                                                  D at e:    
 
                                                  Ti m e:     0 9: 2 4: 1 0  
 
 
                  WI N N O N LI N N O N C O M P A R T M E N T A L A N A L Y SI S P R O G R A M  
                                   7. 0. 0. 2 5 3 5  
                            C or e V er si o n 0 4 J u n 2 0 0 7  
 
S etti n g s  
-------- 
M o d el:  Pl a s m a D at a, E xtr a v a s c ul ar A d mi ni str ati o n  
N u m b er of n o n mi s si n g o b s er v ati o n s:   2 2  
D o s e ti m e:      0. 0 0  
D o s e a m o u nt:      4 5 0. 0 0  
C al c ul ati o n m et h o d:  Li n e ar Tr a p e z oi d al R ul e f or f or I n cr e a si n g V al u e s,  
                     L o g Tr a p e z oi d al R ul e f or D e cr e a si n g V al u e s  
W ei g hti n g f or l a m b d a _ z c al c ul ati o n s:  U nif or m w ei g hti n g  
L a m b d a _ z m et h o d:  Fi n d b e st fit f or l a m b d a _ z,  L o g r e gr e s si o n  
 
 
S u m m ar y T a bl e  
------------- 
      Ti m e         C o n c.      Pr e d.    R e si d u al      A U C       A U M C      W ei g ht  
          h       n g/ m L       n g/ m L       n g/ m L     h* n g/ m L   h* h* n g/ m L  
------------------------------------------------------------------------------- 
     0. 0 0 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 2 5 0 0       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 5 1 6 7       0. 0 0 0 0                           0. 0 0 0 0     0. 0 0 0 0  
     0. 7 5 0 0       0. 5 2 0 0                          0. 0 6 0 6 7    0. 0 4 5 5 0  
Pa ge 2 2 2 of 3 3 1
PI
PI


      1.000        1.150                           0.2694     0.2380 
      1.500        3.220                            1.362      1.733 
      2.000        9.830                            4.624      7.856 
      3.000        14.90                            16.99      40.04 
      4.000        28.70                            38.79      119.8 
      6.000        39.90                            107.4      474.0 
      8.000        61.40                            208.7      1205. 
      12.00        94.70                            520.9      4460. 
      16.00        105.0                            920.3 1.009e+004 
      24.00        172.0                            2028. 3.332e+004 
      36.00        131.0                            3835. 8.704e+004 
      48.00 *      141.0      137.2      3.761      5467. 1.559e+005      1.000 
      60.00 *      101.0      106.6     -5.636      6906. 2.332e+005      1.000 
      72.00 *      83.50      82.86     0.6422      8009. 3.058e+005      1.000 
      96.00 *      52.90      50.03      2.875      9618. 4.395e+005      1.000 
      120.0 *      29.40      30.20    -0.8029 1.058e+004 5.420e+005      1.000 
      144.0 *      17.60      18.23    -0.6350 1.113e+004 6.143e+005      1.000 
      168.0 *      11.30      11.01     0.2906 1.147e+004 6.673e+005      1.000 
 
 
*) Starred values were included in the estimation of Lambda_z. 
 
 
Final Parameters 
--------------- 
Rsq                                                       0.9982 
Rsq_adjusted                                              0.9979 
Corr_XY                                                  -0.9991 
No_points_lambda_z                                        7 
Lambda_z                                1/h               0.0210 
Lambda_z_lower                            h              48.0000 
Lambda_z_upper                            h             168.0000 
HL_Lambda_z                               h              32.9681 
Tlag                                      h               0.5167 
Tmax                                      h              24.0000 
Cmax                                  ng/mL             172.0000 
Cmax_D                             ng/mL/mg               0.3822 
Tlast                                     h             168.0000 
Clast                                 ng/mL              11.3000 
AUClast                             h*ng/mL           11471.7807 
AUCall                              h*ng/mL           11471.7807 
AUCINF_obs                          h*ng/mL           12009.2415 
AUCINF_D_obs                     h*ng/mL/mg              26.6872 
AUC_%Extrap_obs                           %               4.4754 
Vz_F_obs                                  L            1782.2361 
Cl_F_obs                                L/h              37.4711 
AUCINF_pred                         h*ng/mL           11995.4181 
AUCINF_D_pred                    h*ng/mL/mg              26.6565 
AUC_%Extrap_pred                          %               4.3653 
Vz_F_pred                                 L            1784.2900 
Cl_F_pred                               L/h              37.5143 
AUMClast                          h*h*ng/mL          667272.3029 
AUMCINF_obs                       h*h*ng/mL          783128.8994 
AUMC_%Extrap_obs                          %              14.7941 
AUMCINF_pred                      h*h*ng/mL          780149.0860 
AUMC_%Extrap_pred                         %              14.4686 
MRTlast                                   h              58.1664 
MRTINF_obs                                h              65.2105 
MRTINF_pred                               h              65.0373 
AUC0_24                             h*ng/mL            2028.2894 
 
 
 
Page 223 of 331


Wi n N o nli n Pl ot s 
Wi n N o nli n Pl ot s - - T e p oti ni b
T e p oti ni b  
 
Pa ge 2 2 4 of 3 3 1
PI


 
 
Pa ge 2 2 5 of 3 3 1
PI


 
 
Pa ge 2 2 6 of 3 3 1
PI


 
 
Pa ge 2 2 7 of 3 3 1
PI


 
 
Pa ge 2 2 8 of 3 3 1
PI


 
 
Pa ge 2 2 9 of 3 3 1
PI


 
 
Pa ge 2 3 0 of 3 3 1
PI


 
 
Pa ge 2 3 1 of 3 3 1
PI


 
 
Pa ge 2 3 2 of 3 3 1
PI


 
 
Pa ge 2 3 3 of 3 3 1
PI


 
 
Pa ge 2 3 4 of 3 3 1
PI


 
 
Pa ge 2 3 5 of 3 3 1
PI


 
 
Pa ge 2 3 6 of 3 3 1
PI


 
 
Pa ge 2 3 7 of 3 3 1
PI


 
 
Pa ge 2 3 8 of 3 3 1
PI


 
 
Pa ge 2 3 9 of 3 3 1
PI


 
 
Pa ge 2 4 0 of 3 3 1
PI


 
 
Pa ge 2 4 1 of 3 3 1
PI


 
 
Pa ge 2 4 2 of 3 3 1
PI


 
 
Pa ge 2 4 3 of 3 3 1
PI


 
 
Pa ge 2 4 4 of 3 3 1
PI


 
 
Pa ge 2 4 5 of 3 3 1
PI


 
 
Pa ge 2 4 6 of 3 3 1
PI


 
 
Pa ge 2 4 7 of 3 3 1
PI


 
 
Pa ge 2 4 8 of 3 3 1
PI


 
 
Pa ge 2 4 9 of 3 3 1
PI


 
 
Pa ge 2 5 0 of 3 3 1
PI


 
 
Pa ge 2 5 1 of 3 3 1
PI


 
 
Pa ge 2 5 2 of 3 3 1
PI


 
 
Pa ge 2 5 3 of 3 3 1
PI


 
 
Pa ge 2 5 4 of 3 3 1
PI


 
 
Pa ge 2 5 5 of 3 3 1
PI


 
 
Pa ge 2 5 6 of 3 3 1
PI


 
 
Pa ge 2 5 7 of 3 3 1
PI


 
 
Pa ge 2 5 8 of 3 3 1
PI


 
 
Pa ge 2 5 9 of 3 3 1
PI


Wi n N o nli n Pl ot s 
Wi n N o nli n Pl ot s – – T e p oti ni b
T e p oti ni b  M et a b olit e
M et a b olit e  M S C 2 5 7 1 1 0 7 A
M S C 2 5 7 1 1 0 7 A  
 
Pa ge 2 6 0 of 3 3 1
PI


 
Pa ge 2 6 1 of 3 3 1
PI


 
Pa ge 2 6 2 of 3 3 1
PI


 
Pa ge 2 6 3 of 3 3 1
PI


 
Pa ge 2 6 4 of 3 3 1
PI


 
Pa ge 2 6 5 of 3 3 1
PI


 
Pa ge 2 6 6 of 3 3 1
PI


 
Pa ge 2 6 7 of 3 3 1
PI


 
Pa ge 2 6 8 of 3 3 1
PI


 
Pa ge 2 6 9 of 3 3 1
PI


 
Pa ge 2 7 0 of 3 3 1
PI


 
Pa ge 2 7 1 of 3 3 1
PI


 
Pa ge 2 7 2 of 3 3 1
PI


 
Pa ge 2 7 3 of 3 3 1
PI


 
Pa ge 2 7 4 of 3 3 1
PI


 
Pa ge 2 7 5 of 3 3 1
PI


 
Pa ge 2 7 6 of 3 3 1
PI


 
Pa ge 2 7 7 of 3 3 1
PI


 
Pa ge 2 7 8 of 3 3 1
PI


 
Pa ge 2 7 9 of 3 3 1
PI


 
Pa ge 2 8 0 of 3 3 1
PI


 
Pa ge 2 8 1 of 3 3 1
PI


 
Pa ge 2 8 2 of 3 3 1
PI


 
Pa ge 2 8 3 of 3 3 1
PI


 
Pa ge 2 8 4 of 3 3 1
PI


 
Pa ge 2 8 5 of 3 3 1
PI


 
Pa ge 2 8 6 of 3 3 1
PI


 
Pa ge 2 8 7 of 3 3 1
PI


 
Pa ge 2 8 8 of 3 3 1
PI


 
Pa ge 2 8 9 of 3 3 1
PI


 
Pa ge 2 9 0 of 3 3 1
PI


 
Pa ge 2 9 1 of 3 3 1
PI


 
Pa ge 2 9 2 of 3 3 1
PI


 
Pa ge 2 9 3 of 3 3 1
PI


 
Pa ge 2 9 4 of 3 3 1
PI


 
 
Pa ge 2 9 5 of 3 3 1
PI


Wi n N o nli n Pl ot s 
Wi n N o nli n Pl ot s – – T e p oti ni b
T e p oti ni b  M et a b olit e
M et a b olit e  M S C 2 5 7 1 1 0 9 A
M S C 2 5 7 1 1 0 9 A  
 
Pa ge 2 9 6 of 3 3 1
PI


 
 
Pa ge 2 9 7 of 3 3 1
PI


 
 
Pa ge 2 9 8 of 3 3 1
PI


 
 
Pa ge 2 9 9 of 3 3 1
PI


 
 
Pa ge 3 0 0 of 3 3 1
PI


 
 
Pa ge 3 0 1 of 3 3 1
PI


 
 
Pa ge 3 0 2 of 3 3 1
PI


 
 
Pa ge 3 0 3 of 3 3 1
PI


 
 
Pa ge 3 0 4 of 3 3 1
PI


 
 
Pa ge 3 0 5 of 3 3 1
PI


 
 
Pa ge 3 0 6 of 3 3 1
PI


 
 
Pa ge 3 0 7 of 3 3 1
PI


 
 
Pa ge 3 0 8 of 3 3 1
PI


 
 
Pa ge 3 0 9 of 3 3 1
PI


 
 
Pa ge 3 1 0 of 3 3 1
PI


 
 
Pa ge 3 1 1 of 3 3 1
PI


 
 
Pa ge 3 1 2 of 3 3 1
PI


 
 
Pa ge 3 1 3 of 3 3 1
PI


 
 
Pa ge 3 1 4 of 3 3 1
PI


 
 
Pa ge 3 1 5 of 3 3 1
PI


 
 
Pa ge 3 1 6 of 3 3 1
PI


 
 
Pa ge 3 1 7 of 3 3 1
PI


 
 
Pa ge 3 1 8 of 3 3 1
PI


 
 
Pa ge 3 1 9 of 3 3 1
PI


 
 
Pa ge 3 2 0 of 3 3 1
PI


 
 
Pa ge 3 2 1 of 3 3 1
PI


 
 
Pa ge 3 2 2 of 3 3 1
PI


 
 
Pa ge 3 2 3 of 3 3 1
PI


 
 
Pa ge 3 2 4 of 3 3 1
PI


 
 
Pa ge 3 2 5 of 3 3 1
PI


 
 
Pa ge 3 2 6 of 3 3 1
PI


 
 
Pa ge 3 2 7 of 3 3 1
PI


 
 
Pa ge 3 2 8 of 3 3 1
PI


 
 
Pa ge 3 2 9 of 3 3 1
PI


 
 
Pa ge 3 3 0 of 3 3 1
PI


 
 
Pa ge 3 3 1 of 3 3 1
PI