Effect of Inflammation on Pharmacokinetics of Posaconazole
Conditions: Mycoses
Sponsor: University Medical Center Groningen

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Effect of inflammation on pharmacokinetics of 
posaconazole 
(May 2015) 
 
 

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PROTOCOL TITLE 
 Effect of inflammation on pharmacokinetics of posaconazole  
Protocol ID 
PCZ 
Short title 
PCZ & Inflammation 
Version 
001 
Date 
12-05-2015 
Principal investigator(s)  
 
J.W.C. Alffenaar, PharmD, PhD, Associate Professor, 
Clinical Pharmacologist 
Sponsor  
UMCG 
 
 
Subsidising party 
Merck  
Independent expert (s) 
Not applicable 
 
 
 
 
Laboratory sites  
UMCG 
 
 
Pharmacy  
UMCG 
 
 

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Head of Department: 
Prof dr JGW Kosterink 
 
 
 
Principal Investigator: 
Dr JWC Alffenaar 
 
 
 
Co-investigator dept Hematology: 
Dr LFR Span 
 
Drs M Bakker  
 
 
 
Co-investigator 
dept 
Clinical 
Pharmacy 
& 
Pharmacology 
Drs A Veringa 
MSc AG Märtson 
 
 
 
 

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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE .............................................................................. 9 
2. 
OBJECTIVES ................................................................................................................. 9 
3. 
STUDY DESIGN ...........................................................................................................10 
4. 
STUDY POPULATION ..................................................................................................10 
4.1 
Population (base) ..................................................................................................10 
4.2 
Inclusion criteria ....................................................................................................10 
4.3 
Exclusion criteria ...................................................................................................10 
4.4 
Sample size calculation .........................................................................................10 
5. 
TREATMENT OF SUBJECTS .......................................................................................10 
5.1 
Investigational product/treatment ..........................................................................11 
5.2 
Use of co-intervention (if applicable) .....................................................................11 
5.3 
Escape medication (if applicable) ..........................................................................11 
6. 
INVESTIGATIONAL PRODUCT ....................................................................................11 
6.1 
Name and description of investigational  product(s) ..............................................11 
6.2 
Summary of findings from non-clinical studies.......................................................11 
6.3 
Summary of findings from clinical studies ..............................................................11 
6.4 
Summary of known and potential risks and benefits ..............................................11 
6.5 
Description and justification of route of administration and dosage .......................11 
6.6 
Dosages, dosage modifications and method of administration ..............................11 
6.7 
Preparation and labelling of Investigational Medicinal Product ..............................12 
6.8 
Drug accountability ...............................................................................................12 
7. 
NON-INVESTIGATIONAL PRODUCT ...........................................................................12 
7.1 
Name and description of non-investigational product(s) ........................................12 
7.2 
Summary of findings from non-clinical studies.......................................................12 
7.3 
Summary of findings from clinical studies ..............................................................12 
7.4 
Summary of known and potential risks and benefits ..............................................12 
7.5 
Description and justification of route of administration and dosage .......................12 
7.6 
Dosages, dosage modifications and method of administration ..............................12 
7.7 
Preparation and labelling of Non Investigational Medicinal Product .......................12 
7.8 
Drug accountability ...............................................................................................12 
8. 
METHODS ....................................................................................................................12 
8.1 
Study parameters/endpoints .................................................................................12 
8.1.1 
Main study parameter/endpoint .........................................................................12 
8.1.2 
Secondary study parameters/endpoints (if applicable) ......................................12 
8.1.3 
Other study parameters (if applicable) ...............................................................13 
8.2 
Randomisation, blinding and treatment allocation .................................................13 
8.3 
Study procedures ..................................................................................................13 
8.4 
Withdrawal of individual subjects...........................................................................13 
8.4.1 
Specific criteria for withdrawal (if applicable) .....................................................13 
8.5 
Replacement of individual subjects after withdrawal .............................................13 
8.6 
Follow-up of subjects withdrawn from treatment ....................................................13 

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8.7 
Premature termination of the study .......................................................................13 
9. 
SAFETY REPORTING ..................................................................................................13 
9.1 
Section 10 WMO event .........................................................................................14 
9.2 
AEs, SAEs and SUSARs ......................................................................................14 
9.2.1 
Adverse events (AEs) .......................................................................................14 
9.2.2 
Serious adverse events (SAEs) .........................................................................14 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) ...........................14 
9.3 
Annual safety report ..............................................................................................14 
9.4 
Follow-up of adverse events .................................................................................14 
9.5 
Data Safety Monitoring Board (DSMB) / Safety Committee ...................................14 
10. 
STATISTICAL ANALYSIS .........................................................................................14 
10.1 
Primary study parameter(s) ............................. Fout! Bladwijzer niet gedefinieerd. 
10.2 
Secondary study parameter(s) ........................ Fout! Bladwijzer niet gedefinieerd. 
10.3 
Other study parameters ........................................................................................15 
10.4 
Interim analysis (if applicable) ...............................................................................15 
11. 
ETHICAL CONSIDERATIONS ..................................................................................15 
11.1 
Regulation statement ............................................................................................15 
11.2 
Recruitment and consent ......................................................................................15 
11.3 
Objection by minors or incapacitated subjects (if applicable) .................................15 
11.4 
Benefits and risks assessment, group relatedness ................................................16 
11.5 
Compensation for injury ........................................................................................16 
11.6 
Incentives (if applicable) ........................................................................................16 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION ........................16 
12.1 
Handling and storage of data and documents .......................................................16 
12.2 
Monitoring and Quality Assurance.........................................................................16 
12.3 
Amendments .........................................................................................................16 
12.4 
Annual progress report ..........................................................................................16 
12.5 
End of study report ................................................................................................16 
12.6 
Public disclosure and publication policy ................................................................17 
13. 
STRUCTURED RISK ANALYSIS ..............................................................................17 
14. 
REFERENCES .........................................................................................................17 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ABR 
ABR form, General Assessment and Registration form, is the application 
form that is required for submission to the accredited Ethics Committee (In 
Dutch, ABR = Algemene Beoordeling en Registratie) 
AE 
Adverse Event 
AR 
Adverse Reaction 
CA 
Competent Authority 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: 
Centrale Commissie Mensgebonden Onderzoek 
CV 
Curriculum Vitae 
DSMB 
Data Safety Monitoring Board 
EU 
European Union 
EudraCT European drug regulatory affairs Clinical Trials  
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
IMP 
Investigational Medicinal Product  
IMPD 
Investigational Medicinal Product Dossier  
METC  
Medical research ethics committee (MREC); in Dutch: medisch ethische 
toetsing commissie (METC) 
(S)AE 
(Serious) Adverse Event  
SPC 
Summary of Product Characteristics (in Dutch: officiële productinfomatie 
IB1-tekst) 
Sponsor 
The sponsor is the party that commissions the organisation or performance 
of the research, for example a pharmaceutical 
company, academic hospital, scientific organisation or investigator. A party 
that provides funding for a study but does not commission it is not 
regarded as the sponsor, but referred to as a subsidising party. 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
VCZ 
Voriconazole  
Wbp 
Personal Data Protection Act (in Dutch: Wet Bescherming Persoonsgevens) 
WMO 
Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 
 

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SUMMARY 
 
Rationale: Posaconazole is indicated for prophylaxis of invasive aspergillosis and can also 
be used as treatment of several fungal infections. Therapeutic Drug Monitoring (TDM) of 
posaconazole can be performed to maintain efficacy, since exposure-respons relationships 
are described for posaconazole (ref Dolton AAC 2012: mail Marieke). Recently was shown 
that the plasma concentration of another antifungal agent, voriconazole, is influenced by 
inflammation, measured by C-reactive protein value [van Wanrooy et al AAC 2014, Encalada 
Ventura et al AAC 2015; manuscript in preparation of study with clinical trials.gov identifier 
NCT02074462]. During severe inflammation the metabolism of voriconazole is reduced via 
downregulation of cytochrome P450 enzymes, which results in high voriconazole plasma 
concentrations. Subsequently, dosages can be adjusted to avoid toxicity. However, if the 
degree of inflammation decreases again, the metabolism of the drug increases with as a 
result possible subtherapeutic drug concentrations. As posaconazole is only metabolized in 
limited extend by cytochrome P450 enzymes it is likely that posaconazole is not influenced 
by inflammation. However, no published data is available to support the hypothesis that 
exposure of posaconazole is not influenced by inflammation. Data on stable posaconazole 
exposure during treatment will result in a clinical benefit over voriconazole. 
 
Objective: The objective of this study proposal is to determine if posaconazole drug 
exposure is influenced during different stages of inflammation. 
 
Study design: A prospective observational study will be performed at the University Medical 
Center Groningen, the Netherlands to determine if posaconazole drug exposure is influenced 
by inflammation. 
 
Study population: patients receiving posaconazole for treatment or (secondary) prophylaxis 
of fungal infections 
 
Intervention (if applicable): none 
 
Main study parameters/endpoints: Main study parameter is the posaconazole drug 
exposure during different stages of inflammation. Subsequently, a multiple linear regression 
model that describes the contribution of inflammation on posaconazole levels will be 
developed. At last, the relation between the change in CRP and change in drug plasma 
concentration from this study will be compared with the results of our earlier prospective 
voriconazole study [NCT02074462] based on matched patients.  
 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: no risk or burden for the patients as samples from routine patient care 

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are used. Future patients may benefit from the results of this study, as more insight is given 
in the pharmacokinetics of posaconazole.   

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1. INTRODUCTION AND RATIONALE 
 
Invasive aspergillosis (IA) is the leading cause of infection-related death in patients with 
acute leukemia and in hematopoietic stem cell transplant (HSCT) recipients. Various 
pathophysiological changes in severely ill patients, such as cancer patients, can affect the 
pharmacokinetics of antimicrobial agents. Adequate posaconazole drug exposure is 
associated with better treatment outcome. Until recently, posaconazole drug absorption was 
compromised by drug-drug interactions and insufficient food intake. This resulted in 
substantial intra- and interindividual patient variability in the pharmacokinetics of 
posaconazole [Dolton et al AAC 2014, Brüggemann et al CID 2009, Alffenaar et al CID 2009, 
Dolton et al AAC 2012, Vaes et al AAC 2012, Tonini et al AAC 2012]. The introduction of the 
new oral formulation and intravenous preparation improved drug exposure. [Maertens et al 
AAC 2014, Kraft et al AAC 2014].  
 
For voriconazole it was recently shown by our group that metabolism of voriconazole was 
influenced by severe inflammation, measured by C-reactive protein value [van Wanrooy et al 
AAC 2014, Encalada Ventura et al AAC 2015; manuscript in preparation of study with clinical 
trials.gov identifier NCT02074462]. The underlying mechanism was cytokine induced down 
regulation of cytochrome P450 expression. The reduced metabolism resulted in voriconazole 
plasma concentrations exceeding the therapeutic window of voriconazole posing the patient 
at risk for toxicity. Subsequently, dosages were adjusted to remain the voriconazole plasma 
concentration within the therapeutic window. However, when the degree of inflammation 
decreased and thereby the metabolism of voriconazole increased, patients were at risk for 
subtherapeutic drug concentrations. Therefore, it was concluded that inflammation should be 
taken into account when therapeutic drug monitoring of voriconazole is performed.  
 
As posaconazole is only metabolized in limited extend by cytochrome P450 enzymes it is 
likely that posaconazole is not influenced by inflammation. However, no published data is 
available to support the hypothesis that exposure of posaconazole is not influenced by 
inflammation. Data on stable posaconazole exposure during treatment will result in a clinical 
benefit over voriconazole. 
 
2. OBJECTIVES 
 
Primary Objective:  
The objective of this study proposal is to explore the posaconazole drug exposure during 
treatment in different stages of inflammation.  
 
Secondary Objective(s):  
The secondary objective is to develop a multiple linear regression model to describe the 
contribution of inflammation to the variability in posaconazole concentration. Subsequently, 
the relation between change in CRP and change in drug plasma concentration from this 

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study will be compared with the results of our earlier prospective voriconazole study 
[NCT02074462] based on matched patients. 
 
3. STUDY DESIGN 
 
A prospective observational study will be performed at the University Medical Center 
Groningen, the Netherlands using longitudinal data collection to develop a dosing algorithm 
based on data of inflammatory markers and posaconazole concentrations. 
 
4. STUDY POPULATION 
4.1 Population (base)  
Patients that receive posaconazole for treatment or (secondary) prophylaxis of 
fungal infections 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the 
following criteria: 
-aged ≥ 18 yrs  
-receive posaconazole 
-written informed consent 
 
4.3 Exclusion criteria 
 A potential subject who meets any of the following criteria will be excluded from 
participation in this study: 
 
-concomitantly using a strong inhibitor or inducer of CYP P450  
 
4.4 Sample size calculation 
To be able to develop and validate a model based on inflammatory markers and 
posaconazole multiple data points are mandatory. We estimate that it is feasible to 
collect 3-4 data points per treatment week.  
 
Taken into account the non-invasive nature of this study, the routine sampling of 
critically ill patients we plan to recruit 30 patients for this study. 
 
5. TREATMENT OF SUBJECTS 
Subjects receive posaconazole as standard treatment or (secondary) prophylaxis for 
fungal infection. As the treatment with posaconazole and TDM are part of routine care 
they are neither initiated nor altered for study purposes (no intervention). Therefore this 
study is not being subjected to Medical Research Involving Human Subjects Act. Only 
data of standard care and TDM will be collected to develop the dosing algorithm for 
posaconazole during severe inflammation. 

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Attending physicians are allowed to request drug concentration measurement for patient 
care. If the posaconazole concentration is low the attending hospital pharmacist will 
provide the attending physician with a dosage advice. Dosages will be increased if levels 
are too low or decreased if levels are too high. The increase or decrease of the dosage 
will be based on the measured concentration, initial dosage and patient characteristics. 
Follow up will be performed to assure that the level reaches and remains in the 
therapeutic window.  
 
5.1 Investigational product/treatment 
Not applicable 
5.2 Use of co-intervention (if applicable) 
Not applicable 
5.3 Escape medication (if applicable) 
Not applicable 
 
6. INVESTIGATIONAL PRODUCT  
Not applicable; subject receive posaconazole as standard treatment or (secondary) 
prophylaxis for fungal infection 
6.1 Name and description of investigational  product(s) 
Noxafil 100mg Tablet; Noxafil 300mg concentrate for solution for infusion; Noxafil 40 
mg/mL oral suspension  
6.2 Summary of findings from non-clinical studies 
See SmPC of Noxafil 
6.3 Summary of findings from clinical studies 
See SmPC of Noxafil 
6.4 Summary of known and potential risks and benefits 
Non due to the nature of this study 
6.5 Description and justification of route of administration and dosage 
 
Depending on choice of attending physician; IV or PO 
6.6 Dosages, dosage modifications and method of administration 
Depending on choice of attending physician, dosage modifications based on measured 
posaconazole concentrations are part of routine care. 

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6.7 Preparation and labelling of Investigational Medicinal Product 
Not applicable 
6.8 Drug accountability 
Not applicable because Noxafil is not considered a study drug. Data on administration of 
the drug will be collected from the medical chart.  
 
7. NON-INVESTIGATIONAL PRODUCT 
Not applicable 
7.1 Name and description of non-investigational product(s) 
 
Not applicable 
7.2 Summary of findings from non-clinical studies 
Not applicable 
7.3 Summary of findings from clinical studies 
Not applicable 
7.4 Summary of known and potential risks and benefits 
Not applicable 
7.5 Description and justification of route of administration and dosage 
Not applicable 
7.6 Dosages, dosage modifications and method of administration 
Not applicable 
7.7 Preparation and labelling of Non Investigational Medicinal Product 
Not applicable 
7.8 Drug accountability 
Not applicable 
 
8. METHODS 
8.1 Study parameters/endpoints 
8.1.1 Main study parameter/endpoint 
Explore the posaconazole drug exposure during treatment in different stages of 
inflammation. 
8.1.2 Secondary study parameters/endpoints (if applicable) 
Develop a multiple linear regression model that describes the contribution of 
inflammation on posaconazole levels. Compare the relation between change in CRP 

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and change in drug plasma concentration from this study with the results of our 
earlier prospective voriconazole study [NCT02074462] based on matched patients 
drug plasma concentration from this study will be compared with the results of our 
earlier prospective voriconazole study [NCT02074462] based on matched patients. 
8.1.3 Other study parameters (if applicable) 
Not applicable 
8.2 Randomisation, blinding and treatment allocation 
Not applicable 
8.3 Study procedures 
-Patients starting on posaconazole treatment will be evaluated for inclusion. 
-After informed consent is obtained medical data will be collected from the medical 
chart and plasma samples from routine analysis will be obtained.  
 -Samples for posaconazole and inflammatory analysis will be collected 3-4 times 
weekly during treatment. Inflammatory markers like CRP will be determined by the 
department of Clinical Chemistry of the UMCG. Other inflammatory markers of IL-6, 
IL-8 and procalcitonin will not be determined, since these markers are not routinely 
measured. Posaconazole plasma concentrations (trough levels) will be measured 
with a validated and externally tested LC-MS/MS method of analysis [Alffenaar et al J 
Chrom B 2009]. 
 
8.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without 
any consequences.  
8.4.1 Specific criteria for withdrawal (if applicable) 
Not applicable 
8.5 Replacement of individual subjects after withdrawal 
 
Any subject leaving the study will be replaced 
8.6 Follow-up of subjects withdrawn from treatment 
Not applicable 
8.7 Premature termination of the study 
Not applicable 
 
 
9. SAFETY REPORTING 
Because this study proposal does not consider an investigational drug and the use of 
posaconazole and TDM are part of routine care, safety reporting is not subjected to the 
procedures described in the Medical Research Involving Human Subjects Act.  
 

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Because the posaconazole is part of routine care safety reporting will be performed 
according to Dutch Law (‘Geneesmiddelenwet’ in English: Medication Act) to the The 
Netherlands Pharmacovigilance Centre Lareb. 
 
9.1 Section 10 WMO event 
Not applicable 
9.2 AEs, SAEs and SUSARs 
9.2.1 Adverse events (AEs) 
Reporting according to Dutch Law.  
9.2.2 Serious adverse events (SAEs) 
Reporting according to Dutch Law. 
9.2.3 Suspected unexpected serious adverse reactions (SUSARs) 
Reporting according to Dutch Law. 
9.3 Annual safety report 
Not applicable, only for investigational drugs 
9.4 Follow-up of adverse events 
Will be performed in routine patient care 
9.5 Data Safety Monitoring Board (DSMB) / Safety Committee 
Not applicable 
 
10. STATISTICAL ANALYSIS 
Descriptive analysis 
The Mann-Whitney U test (continuous data) and the Fisher’s exact test (binominal data) 
were used to assess possible differences between the patients, in terms of 
demographics, underlying disease, VCZ treatment, laboratory parameters and co-
medication. 
 
10.1 Descriptive statistics 
Demographic characteristics of the patients will be described. Numerical variables will be 
summarized with medians and interquartile range and categorical variables as 
frequencies and percentages.  
 

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10.2 Longitudinal data analysis 
The longitudinal data of the posaconazole concentration will be analyzed with a linear 
mixed model. A log transformation will be performed if the data are not normally 
distributed. A random additive effect will be selected for patients to address different 
concentrations between patients. A first-order autoregressive correlation between 
posaconazole trough concentrations over time will also be selected to correct for 
differences in intervals between observations. To investigate the effect of inflammation on 
posaconazole concentration, the Wald type III test will be conducted after correcting for 
gender, age, posaconazole dose and route of administration, liver enzymes (ALP, ALAT, 
ASAT, γ-GT and total bilirubin) and the use of interacting co-medication. The analysis will 
be performed using SAS 9.3 (SAS Institute Inc., Cary, NC, USA). A p value < 0,05 is 
considered statistically significant. 
 
10.3 Other study parameters 
Not applicable 
10.4 Interim analysis (if applicable) 
Not applicable 
 
11. ETHICAL CONSIDERATIONS 
11.1 Regulation statement 
The study will be conducted according to the principles of the Declaration of Helsinki.  
No approval by the local ethical committee will be required, in accordance with Dutch Law 
(Medical Research Involving Human Subjects Act) due to the nature of this study 
11.2 Recruitment and consent 
After treatment with posaconazole is started by the attending physician, he or she 
informs the patient or representative of the patient, if the patient is not capable of 
giving informed consent, according to article 6 paragraph 1c of the WMO about the 
study. The patient or representative is allowed 48 hours for consideration of 
participation to the study. Written informed consent is obtained from the patient or the 
representative by the research nurse, study physician or investigator. The patient 
information letter and the informed consent form are attached. 
 
11.3 Objection by minors or incapacitated subjects (if applicable) 
In case of impaired consciousness or sedation, the patient is not able to object. The 
representative of the patient, according to article 6 paragraph 1c of the WMO, is then 
asked for informed consent. The representative of the patient is the legal representative, 
or (if no legal representative has been appointed) the person authorized in writing by the 
subject to act on his or her behalf, or (if no such person is available) the subject's spouse, 

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registered partner or other companion in life, thereafter the subjects parents, thereafter 
the subjects adult children and thereafter the adult siblings of the subject. 
11.4 Benefits and risks assessment, group relatedness 
No risks are related to this study as neither investigational drug is administered or 
intervention or invasive is performed. No benefit is expected for the participants.  
11.5 Compensation for injury 
As there is no additional risk for participation in this study, the METC of the UMCG 
granted exemption from liability insurance (art. 4 lid 1 Besluit verplichte verzekering bij 
medischwetenschappelijk onderzoek met mensen). 
11.6 Incentives (if applicable) 
None  
 
12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 Handling and storage of data and documents 
Data and documents are handled confidentially. A subject identification code list is used 
to link the data to the subject. The key to the code is safeguarded by the investigator. The 
investigator and the project leader have access to the source data via a secured data 
folder. The handling of personal data meets the criteria of the dutch Personal Data 
Protection Act (Wbp). 
12.2 Monitoring and Quality Assurance  
Monitoring will be preformed by a QA officer of the department. Written informed consent, 
inclusion & exclusion criteria will be checked for every patient. Data collection will be 
checked for every 5th patient. 
12.3 Amendments  
Amendments are changes made to the research after a favourable opinion by the 
accredited METC has been given. All amendments will be notified to the METC that gave 
a favourable opinion.  
12.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the 
accredited METC once a year. Information will be provided on the date of inclusion of the 
first subject, numbers of subjects included and numbers of subjects that have completed 
the trial, serious adverse events/ serious adverse reactions, other problems, and 
amendments.  
12.5 End of study report 
The investigator will notify the accredited METC of the end of the study within a period of 
8 weeks. The end of the study is defined as the last patient’s last visit.  

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In case the study is ended prematurely, the investigator will notify the accredited METC 
within 
15 
days, 
including 
the 
reasons 
for 
the 
premature 
termination. 
 Within one year after the end of the study, the investigator/sponsor will submit a final 
study report with the results of the study, including any publications/abstracts of the study, 
to the accredited METC.  
12.6 Public disclosure and publication policy 
The results of the study will be published without any restrictions to its content.  
 
13. STRUCTURED RISK ANALYSIS 
Not applicable 
 
14. REFERENCES 
1. Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis: Clinical practice 
guidelines of the infectious diseases society of america. Clin Infect Dis, 2008; 46(3): 327-60.  
2. Dolton MJ, Ray JE, Chen SC, Ng K, Pont LG, McLachlan AJ. Multicenter study of 
voriconazole pharmacokinetics and therapeutic drug monitoring. Antimicrob Agents 
Chemother, 2012; 56(9): 4793-9.  
3. Park WB, Kim NH, Kim KH, et al. The effect of therapeutic drug monitoring on safety and 
efficacy of voriconazole in invasive fungal infections: A randomized controlled trial. Clin Infect 
Dis, 2012; 55(8): 1080-7.  
4. Smith J, Safdar N, Knasinski V, et al. Voriconazole therapeutic drug monitoring. 
Antimicrob Agents Chemother, 2006; 50(4): 1570-2.  
5. Miyakis S, van Hal SJ, Ray J, Marriott D. Voriconazole concentrations and outcome of 
invasive fungal infections. Clin Microbiol Infect, 2010; 16(7): 927-33.  
6. Pascual A, Calandra T, Bolay S, Buclin T, Bille J, Marchetti O. Voriconazole therapeutic 
drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. 
Clin Infect Dis, 2008; 46(2): 201-11.  
7. Pascual A, Csajka C, Buclin T, et al. Challenging recommended oral and intravenous 
voriconazole doses for improved efficacy and safety: Population pharmacokinetics-based 
analysis of adult patients with invasive fungal infections. Clin Infect Dis, 2012; 55(3): 381-90.  
8. Trifilio S, Ortiz R, Pennick G, et al. Voriconazole therapeutic drug monitoring in allogeneic 
hematopoietic stem cell transplant recipients. Bone Marrow Transplant, 2005; 35(5): 509-13.  
9. Trifilio SM, Yarnold PR, Scheetz MH, Pi J, Pennick G, Mehta J. Serial plasma 
voriconazole concentrations after allogeneic hematopoietic stem cell transplantation. 
Antimicrob Agents Chemother, 2009; 53(5): 1793-6.  
10. Weiss J, Ten Hoevel MM, Burhenne J, et al. CYP2C19 genotype is a major factor 
contributing to the highly variable pharmacokinetics of voriconazole. J Clin Pharmacol, 2009; 
49(2): 196-204.  

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11. Jeu L, Piacenti FJ, Lyakhovetskiy AG, Fung HB. Voriconazole. Clin Ther, 2003; 25(5): 
1321-81.  
12. Bruggemann RJ, Alffenaar JW, Blijlevens NM, et al. Clinical relevance of the 
pharmacokinetic interactions of azole antifungal drugs with other coadministered agents. Clin 
Infect Dis, 2009; 48(10): 1441-58.  
13. Morgan ET. Regulation of cytochromes P450 during inflammation and infection. Drug 
Metab Rev, 1997; 29(4): 1129-88.  
14. Theuretzbacher U, Ihle F, Derendorf H. Pharmacokinetic/pharmacodynamic profile of 
voriconazole. Clin Pharmacokinet, 2006; 45(7): 649-63.  
15. Alffenaar JW, Wessels AM, van Hateren K, Greijdanus B, Kosterink JG, Uges DR. 
Method for therapeutic drug monitoring of azole antifungal drugs in human serum using 
LC/MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci, 2010; 878(1): 39-44.  
16. Roffey SJ, Cole S, Comby P, et al. The disposition of voriconazole in mouse, rat, rabbit, 
guinea pig, dog, and human. Drug Metab Dispos, 2003; 31(6): 731-41.