Clinical trial NCT02940730
Conditions: Infectious Peritonitis
Sponsor: University of Colorado, Denver
Start date: 2017-05-01; Completion date: 2018-06-18
Enrollment: 10 participants; Allocation: NON_RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study will evaluate the pharmacokinetic properties of dalbavancin when administered as an intravenous infusion and instilled into the peritoneal space in patients who are undergoing peritoneal dialysis. The patients will receive intravenous dalbavancin followed by intensive plasma and peritoneal dialyses fluid sampling. Following a washout phase, the patients will then receive dalbavancin instilled into their peritoneal space followed by the same intensive plasma and peritoneal dialyses fluid sampling.

Detailed description:
This study is an open label, cross-over study, evaluating the plasma and peritoneal fluid pharmacokinetics (PK) of dalbavancin after either intravenous or intraperitoneal administration. In the first part of the study, ten patients will be administered dalbavancin on study day 0. Pharmacokinetic analysis will be conducted on days 0, 7, and 14. In the second part of the study, the same 10 patients will cross-over and then be administered dalbavancin on study day 0. Pharmacokinetic analysis will be conducted on days 0, 7, and 14.

Sample Size:

Ten (n=10) patients will be evaluated in this pharmacokinetic evaluation. Since this is a descriptive pharmacokinetic study a sample size calculation was not performed

Plasma and peritoneal fluid sampling:

Dalbavancin will be administered on study day 0. On the intravenous administration day dalbavancin will be administered as a 30-minute intravenous (IV) infusion. On the intraperitoneal administration day, dalbavancin will be administered in the peritoneal dialysis fluid with a 6 hour dwell time. On day 0, patients will undergo plasma and peritoneal fluid pharmacokinetic sampling for determination of dalbavancin concentrations at time zero, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, at time of volume exchange. Patients will be given a specimen collection cup and asked to collect \~30 ml of peritoneal dialysate following scheduled nocturnal dwell approximately 24 hours following the administration of dalbavancin administration. Patients will report for a single PK measurement on study days 7 and 14. (18 total plasma and 18 total peritoneal fluid samples per patient). Blood samples will be drawn from a peripherally inserted intravenous catheter. Peritoneal fluid samples will be drawn from the already placed peritoneal dialysis catheter. Blood samples will be immediately centrifuged at 3000g and plasma and peritoneal fluid samples will be stored at -80°C until analysis.

Description, Risks and Justification of Procedures and Data Collection Tools:

Visit 1 and 4: (\~8 hours): On visits 1 and 4 the patients will undergo intensive PK sampling. Subjects will be admitted to the Clinical and Translational Research Center (CTRC) in the morning and a "saline-lock" will be placed. A pre-dose sample and safety labs (comprehensive metabolic panel and urine pregnancy test for women of childbearing potential) will be obtained. The dalbavancin 1500 mg will either be administered intravenously (Visit 1) or into the intraperitoneal space (Visit 4) using the patient's existing peritoneal dialysis catheter with the patients currently prescribed dialysate. Following the blood and peritoneal fluid collection at the second dialysis volume exchange, the subjects will be discharged and asked to return at a scheduled time on day 7. Patients will also be given a specimen collection up with instructions to collect approximately 30 ml of peritoneal dialysate following their evening nocturnal dwell. The collected dialysate will be returned to the investigators.

Visit 2, 3, 5, and 6: (\~60 minutes): A "saline-lock" will be placed and blood and peritoneal fluid sample will be collected at each of these visits. All blood and peritoneal fluid draws will be completed at the CTRC. The patient will be discharged and follow up visits will be scheduled for day 14 or next intensive PK sampling visit.

Washout: During the washout portion of this study the patients will not be asked to come in for any visits. This time-frame is to ensure that all of the medication (dalbavancin) has left the patients' system before administering another dose of the medication.

Laboratory tests: The laboratory tests to be performed as part of this study include pregnancy testing to confirm eligibility and comprehensive metabolic panels to determine eligibility and evaluate safety.

Pharmacokinetic Assessments: 4 mL of blood will be collected in a purple top (Ethylenediaminetetraacetic acid) tube and 4 mL of peritoneal fluid in a urine collection cup at pre-dose, and 1, 2, 3, 4, 6, dialysis volume exchange 1, 8, dialysis volume exchange 2 post dose for quantification of dalbavancin. Blood and peritoneal fluid will be placed in an ice bath to chill until centrifuged. Plasma will be harvested within 30 minutes of each blood sample and will be stored at -80ºC until assaying.

Arms: arm 1: Dalbavancin will be administered via intravenous administration. Patients will undergo plasma fluid pharmacokinetic sampling for determination of dalbavancin concentrations at time zero, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, at time of volume exchange. arm 2: Dalbavancin will be administered as an intraperitoneal administration. Patients will undergo peritoneal fluid pharmacokinetic sampling for determination of dalbavancin concentrations at time zero, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, at time of volume exchange.
Interventions: intervention 1: Dalbavancin via Intravenous Administration intervention 2: Dalbavancin via Intraperitoneal Administration
Intervention descriptions: intervention 1: Patients will undergo plasma fluid pharmacokinetic sampling for determination of dalbavancin concentrations at time zero, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, at time of volume exchange. intervention 2: Patients will undergo peritoneal fluid pharmacokinetic sampling for determination of dalbavancin concentrations at time zero, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, at time of volume exchange.

Protocol documents:
Prot_SAP_000.pdf: 
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w 
COMIRB Protocol 
COLORADO MULTIPLE INSTITUTIONAL REVIEW BOARD 
CAMPUS BOX F-490    TELEPHONE:  303-724-1055  Fax:  303-724-0990 
 
 
 
Protocol #: 
 
16-1355 
Project Title: 
Evaluation of intravenous and intraperitoneal pharmacokinetics of 
dalbavancin in peritoneal dialysis patients 
 
 
Principal Investigator: 
Tyree H. Kiser, PharmD, FCCM, FCCP, BCPS 
Version Date: 
 
10/10/2016 
 
 
 
 
  
 
I. Hypotheses and Specific Aims: 
Hypothesis: 
Dalbavancin maintains adequate plasma and peritoneal fluid concentrations for 2 weeks after a single 
1500 mg dose when administered intravenously or intraperitoneally, making it a viable and convenient 
option for treating peritoneal dialysis patients with peritonitis 
 
Specific Aims: 
1. Determine dalbavancin plasma pharmacokinetics in peritoneal dialysis patients after intravenous and 
intraperitoneal administration 
2. Determine dalbavancin peritoneal fluid pharmacokinetics in peritoneal dialysis patients after intravenous 
and intraperitoneal administration 
3. Evaluate patients for any adverse effects potentially associated with intraperitoneal administration of 
dalbavancin 
 
II. Background and Significance:  
Every year in the United States approximately 110,000-115,000 patients are newly diagnosed with end-
stage renal disease (ESRD) and begin treatment with renal replacement therapy.   Nearly 10,000 of 
these patients are started on peritoneal dialysis (PD).1 The use of home dialysis has increased 
significantly (35% increase) in the last decade, with 95% of home dialysis patients undergoing PD.1 
Infectious peritonitis is a leading major morbidity associated with PD, and it accounts for approximately 
18% of infection-related mortality in PD patients.  Severe or prolonged peritonitis can lead to peritoneal 
membrane failure, ultimately causing technical failure of PD and requiring transition to traditional 
hemodialysis methodologies.  Rapid and effective treatment of peritonitis is required to reduce 
inflammation and preserve peritoneal membrane function.2 The current standard of care involves 
empiric antibiotics covering gram positive organisms as staphylococcus aureus, coagulase negative 
staphylococcus and enterococcus are common infecting pathogens.2 Vancomycin is commonly 
employed at most institutions as there is a risk of MRSA infections in this patient population.  Addition 
of a second drug for gram negative bacteria coverage is recommended until culture and sensitivity 
results are available.  Intravenous or intraperitoneal administration of antibiotics can be utilized; 
however, guidelines recommend the intraperitoneal administration of antibiotics with a dwell time of at 
least 6 hours because it provides instant, high, and sustained concentrations of the antibiotic in the 
peritoneal fluid.2 Although vancomycin covers the majority of gram positive organisms that cause 
peritonitis, its use can be cumbersome in PD patients.  Plasma vancomycin drug concentration 
monitoring must occur to evaluate for vancomycin accumulation.  Additionally, vancomycin must be re-
administered every 3-5 days in order to maintain steady-state trough concentrations around 15 mcg/ml.2 
Similarly to vancomycin, dalbavancin interferes with cell wall synthesis. This is done through binding 
of the D-alanyl-D-alanine terminus of the cell wall peptidoglycan.3 Dalbavancin has been shown to 
rapidly reach therapeutic systemic concentrations and to have an extended half-life of ~8.5 days.4-8 
Dalbavancin has been shown safe and effective with a treatment doses of 1500 mg once or 1000 mg 
followed by a 500 mg dose on day 7.9-11 Dalbavancin pharmacokinetics were evaluated in patients who 
had hepatic or renal impairment. This study showed compared to healthy subjects dalbavancin exposure 
was not increased in mild renal impairment, exposure was ~50% higher in moderate renal impairment, 
100% higher in severe renal impairment, and not significantly different in end stage renal disease 


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patients undergoing dialysis.12 Based on this data only patients with severe renal dysfunction, <30 
mL/min, and not on hemodialysis should have their dalbavancin dose reduced.3 
 
We believe that dalbavancin offers a unique option for PD patients with peritonitis, because it has 
excellent gram positive bacteria coverage, is administered in a single dose option, does not require dose 
adjustment in renal dysfunction on dialysis, and there is no need for routine plasma concentration 
monitoring.  For these reasons, we intend to study the pharmacokinetics of dalbavancin when 
administered intravenously and intraperitoneally in PD patients.   
 
III. Preliminary Studies/Progress Report:   
Dr. Teitelbaum follows 35-40 patients undergoing peritoneal dialysis within his clinic. 
Approximately 95% of the patients followed in his clinic meet inclusion and exclusion 
criteria.  
 
IV. Research Methods 
 
A.  Outcome Measure(s):   
The primary endpoints for the study are to (1) determine dalbavancin plasma pharmacokinetics in 
peritoneal dialysis patients after intravenous and intraperitoneal administration and (2) determin 
dalbavancin peritoneal fluid pharmacokinetics in peritoneal dialysis patients after intravenous and 
intraperitoneal administration. 
Secondary endpoint is to evaluate patients for any adverse effects potentially associated with 
intraperitoneal administration of dalbavancin.   
 
B. Description of Population to be Enrolled:   
Inclusion criteria: 
 
Age ≥18 to ≤89 years of age 
 
Actively receiving chronic peritoneal dialysis (receiving peritoneal dialysis treatments ≥3 
times per week for ≥3 months) 
 
Ability and willingness to provide written informed consent before the first trial ready 
activity 
Exclusion criteria: 
 
Patients currently receiving antimicrobial therapy or have received antibiotic therapy within 
14 days prior to study 
 
Patients with known hypersensitivity reactions to dalbavancin or other glycopeptides 
 
Age <18 years old or >89 years old 
 
Prisoners 
 
Pregnant or breastfeeding women 
 
Decisionally challenged patients: Incompetent to consent, cognitively impaired (e.g. 
psychiatric disorder), altered decisional capacity due to the environment or situation (e.g. 
stress).  
o 
This will be evaluated based on previous medical history given from the patient and 
chart review 
o 
If altered decisional capacity is suspected due to environment or situation follow up 
questions will be asked by clinic personnel not involved with the study or direct care 
of the patient  
 
Patients with active peritonitis 
 
Temperature >38ºC or <36ºC 
 
Significant abdominal tenderness 
 
Child-Pugh class B, or C 
 
C. Study Design and Research Methods   
This study is an open label,  cross-over study, evaluating the plasma and peritoneal fluid 
pharmacokinetics of dalbavancin after either intravenous or intraperitoneal administration.  The 


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patients will be randomly assigned to receive dalbavancin either intravenously or intraperitoneally 
on study visit 1. The patients will receive the alternate administration technique following the 
washout period at visit 4. Patients will be administered dalbavancin either intravenously or 
intraperitoneally on study day 0.  Pharmacokinetic analysis will be conducted on days 0, 7, and 14.  
Following the wash out period of 45 days or greater, the same 10 patients will cross-over and then 
be administered dalbavancin via the alternate administration technique received in visit 1 on study 
day 0.  Pharmacokinetic analysis will be conducted again on days 0, 7, and 14. (see Appendix 1) 
 
Sample Size: 
Ten (n=10) patients will be evaluated in this pharmacokinetic evaluation.  Since this is a descriptive 
pharmacokinetic study a sample size calculation was not performed 
 
Plasma and peritoneal fluid sampling: 
Dalbavancin will be administered on study day 0.  On the intravenous administration day 
dalbavancin will be administered as a 30-minute IV infusion.  On the intraperitoneal administration 
day, dalbavancin will be administered in the peritoneal dialysis fluid with a 6 hour dwell time. On 
day 0, patients will undergo plasma and peritoneal fluid pharmacokinetic sampling for 
determination of dalbavancin concentrations at time zero, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 
at time of volume exchange. Patients will be given a specimen collection cup and asked to collect 
~30 ml of peritoneal dialysate following scheduled nocturnal dwell approximately 24 hours 
following the administration of dalbavancin administration. Patients will report for a single PK 
measurement on study days 7 and 14. (18 total plasma and 18 total peritoneal fluid samples per 
patient).  Blood samples will be drawn from a peripherally inserted intravenous catheter.   Peritoneal 
fluid samples will be drawn from the already placed peritoneal dialysis catheter.  Blood samples will 
be immediately centrifuged at 3000g and plasma and peritoneal fluid samples will be stored at -
80°C until analysis. 
 
D.   Description, Risks and Justification of Procedures and Data Collection Tools: 
Enrollment and Screening: Study subjects will be contacted an enrolled trough Dr. Teitelbaum’s 
clinic. Initial contact will be made by phone prior to a clinic appointment to discuss initial interest of 
the patient. Further information and enrollment will take place at a clinic visit or time of the patients 
choosing. Enrollment will take place in a private room at Dr. Teitelbaum’s clinic. Initial baseline 
and demographic information will be gathered for enrolled patients at the time of enrollment. Safety 
labs (comprehensive metabolic panel and urine pregnancy test for women of childbearing potential) 
will be drawn or performed at Dr. Teitelbaum’s clinic and will coincide with a scheduled clinic visit 
closest to study protocol initiation. The comprehensive metabolic panel will be drawn to evaluate 
Child-Pugh score if there is no comprehensive metabolic panel within the medical record within 30 
days of protocol initiation.  
 
Visit 1 and 4: (~8 hours): On visits 1 and 4 the patients will undergo intensive PK sampling. 
Inclusion and exclusion criteria will be reviewed with the patient at each visit prior to initiation of 
the protocol. Subjects will be admitted to the CTRC in the morning and a “saline-lock” will be 
placed. The dalbavancin preparations will be prepared and managed by Dr. Kiser or Dr. Van Matre 
who are both clinical pharmacists with training in sterile drug preparation. The dalbavancin 1500 
mg will either be administered, by CTRC nursing staff, intravenously (as randomly assigned) or into 
the intraperitoneal space (as randomly assigned) using the patient’s existing peritoneal dialysis 
catheter with the patients currently prescribed dialysate. Following the blood and peritoneal fluid 
collection at the second dialysis volume exchange, the subjects will be discharged and asked to 
return at a scheduled time on day 7. Patients will also be given a specimen collection up with 
instructions to collect approximately 30 ml of peritoneal dialysate following their evening nocturnal 
dwell. The collected dialysate will be returned to the investigators. 
 
Visit 2, 3, 5, and 6: (~60 minutes): A “saline-lock” will be placed and a single blood and peritoneal 
fluid sample will be collected at each of these visits. All blood and peritoneal fluid draws will be 


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completed at the outpatient CTRC. The patient will be discharged and follow up visits will be 
scheduled for day 14 or next intensive PK sampling visit.   
 
Washout: During the 45 day or greater washout portion of this study the patients will not be asked 
to come in for any visits. This timeframe, which is greater than 5 half-lives of dalbavancin, is to 
ensure that all of the medication (dalbavancin) has left the patients’ system before administering 
another dose of the medication. 
 
Laboratory tests:  The laboratory tests to be performed as part of this study include pregnancy 
testing to confirm eligibility and comprehensive metabolic panels if one is not documented within 
30 days prior to the initiation of protocol to determine Child-Pugh score. These will be done at an 
initial screening visit if required to coincide with clinic appointment before visit 1.     
 
Pharmacokinetic Assessments: 4 mL of blood will be collected in a purple top (EDTA) tube and 4 
mL of peritoneal fluid in a urine collection cup at pre-dose, and 1, 2, 3, 4, 6, dialysis volume 
exchange. Blood and peritoneal fluid will be placed in an ice bath to chill until centrifuged. Plasma 
will be harvested within 30 minutes of each blood sample and will be stored at -80ºC until assaying. 
 
Sample Coding and Storage:  Study samples will be coded with an indirect identifier and stored in 
Dr. Kiser’s access-controlled laboratory. 
 
Safety Assessments: 
All clinical and laboratory adverse events will be graded according to the Common Terminology 
Criteria for Adverse Events v4.0 as outlined in Appendix 3.  All patient reported adverse events will 
be evaluated. The most common reactions seen with dalbavancin to date are nausea, vomiting, 
diarrhea, headache, rash, and pruritis. For patients on study protocol following both intravenous and 
intraperitoneal dalbavancin administration, in the event of grade 2 or higher clinical or laboratory 
adverse events, these will be reported to the study physician, Dr. Isaac Teitelbaum or the study 
safety officer Dr. Seth Furgeson within 24 hours and the need for and type of follow-up care will be 
determined by Dr. Isaac Teitelbaum or Dr. Seth Furgeson (e.g., physician evaluation, follow-up 
labs, discontinuation of study medication, etc).  Subjects will be discontinued from study for any 
grade 3 or 4 adverse events associated with dalbavancin administration. 
 
Risks of Procedures:  
 
Side effects of dalbavancin include: 
 
Most Common 
 
Nausea (5.5%) 
 
Vomiting (2.8%) 
 
Diarrhea (4.4%) 
 
Headache (2.7%) 
 
Rash (2.7%) 
 
Pruritus (2.1%) 
 
Less Common (Less than 2% of patients) 
 
Anemia, hemorrhagic anemia, leucopenia, neutropenia, thrombocytopenia, petechiae, 
eosinophilia, thrombocytosis, gastrointestinal hemorrhage, melena, hematochezia, 
abdominal pain, infusion-related reactions, hepatotoxicity, anaphylactic reaction, 
Clostridium difficile colitis, oral candidiasis, vulvovaginal mycotic infection, hepatic 
transaminases increased, blood alkaline phosphatase increased, international normalized 


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ratio increased, blood lactate dehydrogenase increased, gammaglutamyl transferase 
increased, hypoglycemia, dizziness, bronchospasm, flushing, phlebitis, wound hemorrhage, 
spontaneous hematoma 
 
It is not expected that patients will have all of these side effects. Other side effects may occur that 
were not seen before. Side effects are usually temporary and manageable. However, it is possible 
that these side effects could be serious or fatal. 
 
Risk of development of drug-resistant bacteria 
Receiving dalbavancin in the absence of a proven or strongly suspected bacterial infection increases 
the risk of the development of drug-resistant bacteria. Currently there are no reported cases of 
dalbavancin resistance reported within the literature. Dalbavancin also shows extremely high 
potency against medically important Staphylococcal and Streptococcal species, including 
methicillin resistant Staphylococcus aureus.13-15To date in vitro dalbavancin resistance has not been 
induced but possible mutations have increased the minimum inhibitory concentration.16,17 This has 
not been seen clinically, and we will maximize the minimum inhibitory concentration to area under 
the curve ratio, utilizing the 1500 mg dosing strategy.  
 
Risk of Blood Draw 
During the two long study visits a hollow needle/plastic tube will be placed in each patient’s arm for 
taking blood samples and will be left in arm until the last blood draw.  There may be some minor 
discomfort associated with the needle/plastic tube taped to arm. In about 1 in 10 cases, a small 
amount of bleeding under the skin will produce a bruise. The risk of a blood clot forming in the vein 
is about one in 100, while the risk of infection or significant blood loss is one in 1000. 
    
E.   Potential Scientific Problems:   
We have given careful consideration to potential obstacles in conducting this study and how we will 
address them. Recruitment. Subjects will be recruited through current clinical relationships through 
Dr. Isaac Teitelbaum’s clinical practice at the University of Colorado Hospital. Dr. Teitelbaum is 
responsible for the management of a significant number of patients requiring peritoneal dialysis 
through his clinic. Retention. Subject compensation is distributed over the course of the study to 
encourage continued participation. Generalizability to peritoneal dialysis patients with peritonitis. 
This study must be performed in non-infected volunteers as the dalbavancin pharmacokinetic profile 
and therapeutic efficacy for the treatment of peritonitis is not currently established. Also it is unclear 
if the pharmacokinetics of dalbavancin in non-infected volunteers undergoing peritoneal dialysis 
would be the same as patients undergoing peritoneal dialysis with active peritonitis. The 
pharmacokinetic profiles between non-infected volunteers and patients with acute bacterial skin and 
skin structure infections were previously found to be similar. 
 
F.   Data Analysis Plan:   
Dalbavancin concentration measurements: 
Dalbavancin concentration analysis will be performed utilizing a LC with MS/MS utilizing a 
previously published method18 at the Medicinal Chemistry Core, run by Dr. Michael Wempe, part of 
the University of Colorado Center for Translational Pharmacokinetics and Pharmacogenomics.  The 
center laboratory is a Clinical Laboratory Improvements Amendments (CLIA) certified laboratory.  
Dr. Kiser is a member of this center and will oversee all data processing and analysis. 
 
 
Pharmacokinetic analysis:  
Plasma and peritoneal fluid concentration-time data for dalbavancin will be evaluated using a multi-
compartment model in Phoenix WinNonlin (Pharsight corporation).  One, two, and three 
compartment models will be explored.  The following PK parameters will be calculated for plasma 
and dialysate samples:  Cmax – measured, Tmax – measured, Cmin – measured.  Fraction of 
intraperitoneal (IP) dose absorbed [(Dose – drug concentration remaining in dialysate at end of 


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antibiotic dwell)/Dose].  Kel – elimination rate constant.  T1/2 – 0.693/Kel.  Kpc0-6 – rate constant 
for distribution of dalbavancin from peritoneal cavity between 0-6 hours.  Distribution half-life in 
the peritoneal cavity between 0-6 hours (t1/2 = ln2/kpc0-6).  Clearance systemic = (FxDose)/AUC0-
infinity. Clearance peritoneal – dalbavancin concentration in spent dialysate/AUC of peritoneal 
fluid.  Non-dialysis clearance – Cl= Clplasma – Clperitoneal.  AUC0-infinity – linear trapezoidal 
method.  AUC0-12 hours – linear trapezoidal method.  Volume of distribution for each 
compartment – Cl/kel; nonsteady state equations will be utilized.   The ratio of plasma dalbavancin 
to dialysate plasma concentration at each time point – Cplasma/Cdialysate and via 
AUCplasma/AUCdialysate.  Given the sample size of 10 patients completing each treatment 
modality we will be able to calculate means and standard deviations for all included 
pharmacokinetic parameters. We will incorporate the dalbavancin PK parameters into a nonlinear 
mixed effects model (NONMEM) or ADAPT II to determine the pharmacokinetics and examine the 
effects of varying dosing strategies on plasma and peritoneal fluid concentrations.   
 
Analysis of pharmacodynamic targets:  
Pharmacodynamic parameters will be evaluated in order to determine whether dalbavancin dosing 
results in initial and steady-state plasma and peritoneal concentrations that are adequate for 
treatment of infections due to common pathogens (Staph aureus, Coag neg staph, and enterococcus). 
Monte Carlo simulation (Crystal Ball version 7, Decisioneering, Inc., Denver, CO) will be used in 
this study to calculate probability of target attainment (PTA) for pharmacodynamic goals. The 
model randomly applies values for Cmax and AUC0-12 derived from data obtained from the study 
patients.  We will utilize CLSI and EUCAST MIC data for the common gram positive pathogens.  
We will place these MIC distributions into our Monte Carlo simulation for comparison to 
dalbavancin plasma concentrations and PK variability.  From these studies, MIC frequency 
distributions will be constructed and used in the Monte Carlo simulations. Ten thousand simulations 
will be performed at each MIC value and for each of the selected pathogens.     
 
  
Statistical comparisons of PK/PD findings 
Intra-patient pharmacokinetics and pharmacodynamics of dalbavancin will be 
compared between intravenous and intraperitoneal administration using the paired-
test.  Given the sample size of 10 patients completing each phase of the study, we 
will be able to detect a mean difference in area under the curve between the two 
treatment modalities of 1527 mghr/L at a power of 80%. Probability of target 
obtainment will be compared with the paired t-test.  Statistical comparisons will be 
compared using SAS version 9.3.  A p-value < 0.05 will be considered significant. 
 
G.  Summarize Knowledge to be Gained:   
This study will determine the pharmacokinetic profile of dalbavancin within the plasma and 
peritoneal fluid following the administration of dalbavancin intravenously and then intraperitonealy 
in patients undergoing peritoneal dialysis. This study may also identify possible side effects from 
intraperitoneal administration of dalbavancin. Determining the pharmacokinetic profile and side 
effect profile of dalbavanicin in patients undergoing peritoneal dialysis may allow for further 
treatment applications of dalbavanicin including peritonitis.  
 
 
 


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Appendix 1: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 0 
Intravenous 
Dalbavancin 1500 mg 
x1 
PK analysis 
Day 7 
PK analysis 
 
Minimum additional 45 day washout 
after Day 14 PK analysis 
Day 0 
Intraperitoneal 
Dalbavancin 1500 
mg x 1 
PK analysis 
Day 14 
PK analysis 
Day 14 
PK analysis 
Day 7 
PK analysis 


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Appendix 2. Schedule of Events 
 
Blood Volume 
(mL) 
Tube 
Type 
Visit 
1 
Visit 
2 
Visit 
3 
Washout 
Visit 
4 
Visit 
5 
Visit 
6 
Duration (days) 
 
 
1 
1 
1 
At least 
45 
1 
1 
1 
Consent 
 
 
x 
 
 
 
 
 
 
CMP 
7 
Green 
x 
 
 
 
x 
 
 
Urine pregnancy test 
 
 
x 
 
 
 
x 
 
 
Study drug administration 
 
 
x 
 
 
 
x 
 
 
Intensive Pharmacokinetic Sampling (4 mL for each drug in 
purple top tubes) 
36 
Purple 
x 
 
 
 
x 
 
 
Follow up Pharmacokinetic Sampling  
4 
Purple 
 
x 
x 
 
 
 
 
Clinical Adverse Events Assessed 
 
 
x 
x 
x 
 
x 
x 
x 
Blood volume (mLs)b 
 
 
43 
4 
4 
 
43 
4 
4 
 


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Appendix 3: Adverse drug reaction grading  
 
Description  
Grade 1 
Mild  ; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL 
Grade 3 
Sever or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL 
Grade 4 
Life-threatening consequences; urgent intervention indicated 
Grade 5 
Death related to adverse event  
Complete descrition of grading for each system organ class can be found through the U.S. Department of Health and Human Services,National Institutes of 
Health, and National Cancer Institute at the following web address. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_40 
 


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H. References: 
 
 
1. 
2016 USRDS Annual Data Report.  
2. 
Li PK, Szeto CC, Piraino B, et al. Peritoneal dialysis-related infections recommendations: 2010 update. Peritoneal dialysis international 
: journal of the International Society for Peritoneal Dialysis 2010;30:393-423. 
3. 
Dalvance(R) [package insert]. Durata Therapeutics U.S. Limited, Parsippany, NJ; January 2016.  
4. 
Buckwalter M, Dowell JA. Population pharmacokinetic analysis of dalbavancin, a novel lipoglycopeptide. Journal of clinical 
pharmacology 2005;45:1279-87. 
5. 
Dorr MB, Jabes D, Cavaleri M, et al. Human pharmacokinetics and rationale for once-weekly dosing of dalbavancin, a semi-synthetic 
glycopeptide. The Journal of antimicrobial chemotherapy 2005;55 Suppl 2:ii25-30. 
6. 
Dowell JA, Goldstein BP, Buckwalter M, Stogniew M, Damle B. Pharmacokinetic-pharmacodynamic modeling of dalbavancin, a novel 
glycopeptide antibiotic. Journal of clinical pharmacology 2008;48:1063-8. 
7. 
Leighton A, Gottlieb AB, Dorr MB, et al. Tolerability, pharmacokinetics, and serum bactericidal activity of intravenous dalbavancin in 
healthy volunteers. Antimicrobial agents and chemotherapy 2004;48:940-5. 
8. 
Nicolau DP, Sun HK, Seltzer E, Buckwalter M, Dowell JA. Pharmacokinetics of dalbavancin in plasma and skin blister fluid. The 
Journal of antimicrobial chemotherapy 2007;60:681-4. 
9. 
Boucher HW, Wilcox M, Talbot GH, Puttagunta S, Das AF, Dunne MW. Once-weekly dalbavancin versus daily conventional therapy for 
skin infection. The New England journal of medicine 2014;370:2169-79. 
10. 
Dunne MW, Puttagunta S, Giordano P, Krievins D, Zelasky M, Baldassarre J. A Randomized Clinical Trial of Single-Dose Versus 
Weekly Dalbavancin for Treatment of Acute Bacterial Skin and Skin Structure Infection. Clinical infectious diseases : an official 
publication of the Infectious Diseases Society of America 2016;62:545-51. 
11. 
Jauregui LE, Babazadeh S, Seltzer E, et al. Randomized, double-blind comparison of once-weekly dalbavancin versus twice-daily 
linezolid therapy for the treatment of complicated skin and skin structure infections. Clinical infectious diseases : an official publication 
of the Infectious Diseases Society of America 2005;41:1407-15. 
12. 
Marbury T, Dowell JA, Seltzer E, Buckwalter M. Pharmacokinetics of dalbavancin in patients with renal or hepatic impairment. Journal 
of clinical pharmacology 2009;49:465-76. 
13. 
Biedenbach DJ, Ross JE, Fritsche TR, Sader HS, Jones RN. Activity of dalbavancin tested against Staphylococcus spp. and beta-
hemolytic Streptococcus spp. isolated from 52 geographically diverse medical centers in the United States. Journal of clinical 
microbiology 2007;45:998-1004. 
14. 
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