Conditions: Peritoneal Dialysis-associated Peritonitis
Keywords: Vancomycin Pharmacokinetics Pharmacodynamics Automated Peritoneal Dialysis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 4
Healthy volunteers: no

Brief summary:
Vancomycin is the most commonly used empiric treatment for infectious peritonitis in patients on peritoneal dialysis. Current dosing and monitoring for safety and efficacy is empiric, especially for those on rapid-cycling modalities. The goal of this study is to understand the pharmacokinetics of vancomycin in patients on rapid-cycling peritoneal dialysis modalities in order to derive an optimal dosing regimen.

Detailed description:
Peritoneal dialysis (PD) is a form of renal replacement therapy indicated for those with acute kidney injury or end stage renal disease. Currently, two modalities of PD exist and is individualized based on patient and life-style specific factors. Continuous ambulatory peritoneal dialysis (CAPD) allows 4 - 5 exchanges performed manually whereas automated peritoneal dialysis (APD) involves continuous, automated, cyclical exchanges performed by a device at home during the night. Peritonitis is a common complication in PD and accounts for a large portion of hospital readmission and mortality. Vancomycin is the most common antibiotic recommended and has notable gram-positive coverage used empirically during suspected peritonitis.

Despite widespread use, vancomycin lacks good pharmacokinetic characterization in PD. Early pharmacokinetic studies using vancomycin were conducted predominantly in patients on CAPD on glucose-based prescriptions. Data is non-existent in PD patients administered the novel dialysate solution icodextrin, or those treated with overnight APD. The impact of residual kidney function (RKF) on vancomycin in PD is also lacking. Enhanced vancomycin clearance in RKF may result in under-dosing, while overdosing may result in nephrotoxicity and loss of clinically important RKF.

The investigators will characterize the pharmacokinetic profile of vancomycin following a single intraperitoneal dose of vancomycin in icodextrin dialysate to non-infected PD patients and examine the relationship between RKF and vancomycin clearance using serum, dialysate and urine. The goal is to use this data in non-infected subjects to generate information to guide vancomycin dosing in patients on rapid-cycling PD modalities.

Arms:
arm 1: A single 20 mg/kg intraperitoneal dose in 1-liter of 7.5% icodextrin solution of vancomycin will be administered. Sparse blood sampling will be obtained during an overnight 12-hour dwell and during the exchange period.

Interventions: intervention 1: Vancomycin
Intervention descriptions: intervention 1: Vancomycin one-time 20 mg/kg intraperitoneal dose.

Protocol document:
Prot_SAP_000.pdf: 
Pharmacokinetics of Vancomycin in Automated Peritoneal Dialysis  
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1 
Version History 
2 
Version 
Date 
Change History 
1.0 
13 December 2017 
Concept Protocol 
1.1 
04 January 2018 
Draft Protocol 
2.0 
03 February 2018 
Protocol 
3.0 
14 September 2018 
Protocol Revision 
4.0 
15 January 2019 
Amendment- Clarification of 
post-study follow-up, 
addition of serum creatinine 
analysis, and clarification on 
sampling points  
 
3 
 
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8 
Abbreviations 
9 
 
10 
APD 
Automated Peritoneal Dialysis 
AUC 
Area Under Concentration-Time Curve 
CAPD 
Continuous Ambulatory Peritoneal Dialysis  
ESRD 
End Stage Renal Disease 
MIC 
Minimum Inhibitory Concentration 
NCA 
Non-Compartmental Analysis  
PET 
Peritoneal Equilibration Test 
PK 
Pharmacokinetics 
PD 
Peritoneal Dialysis 
 
11 
Clinical Study Title 
A prospective, single-site, open-label, pharmacokinetic study of 
intermittent intraperitoneal vancomycin in adult subjects receiving 
automated peritoneal dialysis (APD) 
Clinical Study Site 
Thomas Jefferson University, Philadelphia, PA 
Principal 
Investigator  
Walter K. Kraft, M.D.  
Department of Pharmacology & Experimental Therapeutics  
Thomas Jefferson University Hospital  
132 S. 10th Street, 1170 Main Building  
Philadelphia, PA 19107 
Co-Investigators 
Edwin Lam, Pharm.D. 
Jingjing Zhang, M.D., Ph.D. 
Protocol Date 
13 December 2017 
NCT 
NCT03685747 


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Table of Contents 
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13 
 
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1. INTRODUCTION ......................................................................................................................................... 3 
15 
2. STUDY OBJECTIVES .................................................................................................................................... 5 
16 
2.1 
Primary Objective.......................................................................................................................... 5 
17 
2.2 
Secondary Objectives ................................................................................................................ 5 
18 
3. STUDY DESIGN ........................................................................................................................................... 5 
19 
3.1 
Overview and Design .................................................................................................................... 5 
20 
3.2 
Schedule & Procedures ............................................................................................................. 7 
21 
4. STUDY POPULATION ............................................................................................................................... 10 
22 
4.1 
Inclusion Criteria ......................................................................................................................... 10 
23 
4.2 
Exclusion Criteria ..................................................................................................................... 10 
24 
5. STUDY ENDPOINTS .................................................................................................................................. 10 
25 
5.1 Primary Pharmacokinetic Endpoint .................................................................................................. 10 
26 
5.2 Secondary Pharmacokinetic Endpoints ......................................................................................... 11 
27 
6. MEASUREMENTS AND EVALUATIONS .................................................................................................... 11 
28 
6.1 
Study Data ................................................................................................................................... 11 
29 
6.2  
Plasma Samples ....................................................................................................................... 11 
30 
7. SAMPLE SIZE AND ANALYSIS PLAN .......................................................................................................... 12 
31 
8.1 
Sample Size ................................................................................................................................. 12 
32 
8.2 
Statistical and Pharmacokinetic Analysis ................................................................................ 12 
33 
8. DATA COLLECTION AND MANAGEMENT PLAN ....................................................................................... 12 
34 
8.1  
Database System Overview ........................................................................................................ 12 
35 
8.2 
Case Report Forms and Data Entry ......................................................................................... 12 
36 
9. SAFETY ..................................................................................................................................................... 12 
37 
10. REFERENCES .......................................................................................................................................... 13 
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1. INTRODUCTION 
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Peritoneal dialysis (PD) is a form of renal replacement therapy indicated for those with acute 
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kidney injury or end stage renal disease (ESRD). In 2013 PD was utilized in approximately 7% of 
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the 660,000 prevalent patients with ESRD in the United States. Within that time, the prevalence 
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of PD has seen an increase by over 30% between 2007 – 2014.1 During PD, a hyperosmolar 
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solution is introduced into the peritoneal cavity allowing solute exchange between the dialysate-
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contained in the cavity and blood from the perfused peritoneum. A concentration gradient is thus 
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created allowing ultrafiltration and diffusional clearance of toxic materials. PD fluids are available 
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as glucose-based or non-glucose based solutions. Commonly prescribed glucose-based PD 
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solutions have been associated with peritoneal membrane injury and negative systemic effects 
55 
leading to suboptimal patient and technique survival. On the other hand, newer non-glucose 
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based solution marketed in the United States have shown to improve fluid removal during long 
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dialysis exchanges and offer greater peritoneal membrane protection.2   
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Principles of Peritoneal Dialysis 
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Currently, two modalities of PD exist and is individualized based on patient and life-style specific 
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factors. Continuous ambulatory peritoneal dialysis (CAPD) allows 4 – 5 exchanges performed 
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manually whereas automated peritoneal dialysis (APD) involves continuous, automated, cyclical 
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exchanges performed by a device at home during the night.3 APD offers advantages over CAPD 
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by allowing fluid-free or “dry” daytime dwells thereby permitting those who require PD liberty 
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for their activities of daily living. In addition, several other advantages such as lower incidences 
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of infection and hernias, enhanced solute clearances, and positive psychosocial impact have been 
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reported.3 Overall, the prevalence of APD has been increasing throughout the years as the 
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number of patients utilizing CAPD declines.4  
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Vancomycin in Peritoneal Dialysis  
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Peritonitis is a common complication in PD and accounts for a large portion of hospital 
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readmission and mortality.1,5 In addition, severe or prolonged peritonitis can lead to membrane 
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failure prompting the switch from PD to hemodialysis. The International Society of Peritoneal 
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Dialysis (ISPD) recommends intraperitoneal administration as the preferred route to deliver 
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antibiotics in the absence of systemic bacteremia.5 Vancomycin is the most common antibiotic 
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recommended and has notable gram-positive coverage used empirically during suspected 
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peritonitis.   
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Rationale for the Proposed Study  
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Vancomycin is eliminated unchanged in the urine through glomerular filtration and is best 
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characterized by a distribution and elimination phase following parenteral administration. 
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Vancomycin’s bactericidal activity is considered time-dependent with the ratio of the 24-hour 
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area-under-the-concentration (AUC) versus time/minimal-inhibitory concentration (MIC) ratio 
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(AUC/MIC) being the best pharmacokinetic/pharmacodynamic predictor of effectiveness. The 
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preferred AUC/MIC ratio is > 400. Dosing in the range of 15-30 mg/kg is recommended by several 
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professional societies including ISPD to maintain a serum concentration level of 15 mg/L in order 
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to maximize efficacy and reduce toxicity, although this trough is only loosely correlated with 
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corresponding AUC/MIC.5,6 Furthermore, the evidence supporting this recommended trough is 
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essentially nonexistent in PD patients on APD, where data on vancomycin bioavailability and 
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clearance with varying degrees of peritoneal function is sparse. In addition, early 
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pharmacokinetic studies were conducted only in patients on CAPD modalities, glucose-based 
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prescriptions, or those on intravenous vancomycin.7-9  Lastly, the relationship between serum 
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concentration and site of action at the peritoneal cavity wall is not established. In totality, the 
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goal is to close the knowledge gap in this very common use of vancomycin.  
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Although the ISPD advisory committee on peritonitis management recommends a 25% increase 
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in antibiotic dose in non-anuric patients, residual kidney function may affect the exposure, 
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clearance, distribution and serum half-life for those antibiotics administered. This however is an 
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empiric recommendation and there is no formal quantification of how residual kidney function 
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(RKF) may impact pharmacokinetics. The impact on RKF on vancomycin in PD is also lacking. RKF 
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is critical for the welfare and survival of PD patients. Indeed, 2 large multicenter studies, the 
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Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD-2) (AJKD;41:1293-2302, 
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2003) and the Canada/USA Peritoneal Adequacy Study (CANUSA) (JASN, 12:2158-2162, 2001), 
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both have shown statistically significant (by multivariable analyses) 12% reductions in mortality 
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per ml/min/1.73 m2 residual GFR increase or per 5L/week residual GFR increase, respectively.  
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Hence, it is important to assess vancomycin pharmacokinetics in PD patients with RKF for two 
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reasons. First, the enhanced vancomycin clearance of RKF may result in under-dosing and 
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secondly, overdosing may result in nephrotoxicity and loss of critically important RKF. This 
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presents a challenge when considering the bi-exponential pharmacokinetic behavior of 
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vancomycin and produces a significant source of variability allowing controversy in the role of 
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monitoring serum vancomycin in patients on APD.10,11 
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Interestingly, a recent retrospective analysis examining residual renal function and peritonitis 
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outcomes show that the odds of peritonitis treatment failure for those with urinary creatinine 
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clearances of greater than 5 mL/min were greater when compared to those who were anuric.12 
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These associations further challenge the need for optimal vancomycin dosing strategies in 
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patients on rapid-cycling modalities to maximize the efficacy, safety, and cost.   
115 
Moreover, icodextrin a non-glucose based PD fluid, is an increasingly used PD dialysate solution 
116 
to complement conventional glucose-based PD fluids. Commonly prescribed glucose-based PD 
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solutions have been associated with peritoneal membrane injury and negative systemic effects 
118 
leading to suboptimal patient and technique survival. Non-glucose based solutions such as 
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icodextrin marketed in the United States have shown to improve fluid removal during long 
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dialysis exchanges and offer greater peritoneal membrane protection.  In-vitro studies conducted 
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with 7.5% icodextrin demonstrate physical compatibility and chemical stability, however there is 
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a lack of information for the clearance, stability and effect on the minimum inhibitory 
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concentration of vancomycin in-vivo.13 As there will be increasing use of icodextrin, 
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characterization of vancomycin pharmacokinetics will be important. 
125 
Therefore, this current study aims to explore the pharmacokinetics and pharmacodynamics of 
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intraperitoneal administered vancomycin in un-infected subjects on APD and explore the in-vivo 
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behavior of vancomycin in 7.5% icodextrin PD solution.    
128 
2. STUDY OBJECTIVES 
129 
2.1 
Primary Objective  
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 Characterize the pharmacokinetic profile of vancomycin in serum, urine, and dialysate 
131 
following a single intermittent intraperitoneal dose of vancomycin in non-infected 
132 
patients on automated peritoneal dialysis  
133 
2.2 
Secondary Objectives 
134 
 Examine the relationship between residual kidney function and vancomycin clearance 
135 
using serum, dialysate and urine  
136 
 Describe the safety, tolerability, and stability of intraperitoneal vancomycin when 
137 
administered in a 7.5% icodextrin-containing dialysis solution  
138 
2.3  
Exploratory Objectives 
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 Investigate dosing recommendations and adjustments based on population 
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pharmacokinetic parameters generated from serum and dialysate concentrations in adult 
141 
patients on APD 
142 
 Correlate the peritoneal transport function, measured using the peritoneal equilibration 
143 
test (PET), to vancomycin pharmacokinetics  
144 
 Correlate dialysis adequacy, measured as a function of peritoneum urea clearance, time, 
145 
and volume of dialyzer fluid (Kt/V), to vancomycin pharmacokinetics  
146 
3. STUDY DESIGN 
147 
3.1 
Overview and Design 
148 
This is a prospective, single-site, open-label, pharmacokinetic study of vancomycin in infection-
149 
negative healthy adult patients on peritoneal dialysis. Prospective patients will be identified 
150 
through Thomas Jefferson University Hospital nephrology practice. Subjects will be asked to 
151 
consent prior to participation in the study. The majority of research activities will take place at 
152 
the Thomas Jefferson University Clinical Research Unit (CRU). 
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Subjects will be on an APD regimen consisting of a 12-hour overnight dwell followed by a 9-hour 
155 
on-cycler exchange (figure 1). Vancomycin will be administered via intraperitoneal injection in 1 
156 
liter of icodextrin solution. There will be 4 exchanges during the 9-hour exchange period. A sparse 
157 
sampling approach will be used in collecting blood samples. A total of 16 blood samples will be 
158 
collected.  
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Figure 1. Schematic depiction of APD regimen.  
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3.2 
Schedule & Procedures 
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A schematic is illustrated in figure 2 and study procedure detailed in table 1.   
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Figure 2. Study day and sampling schematic 
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              x5   
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      x4           x4     x4       x4      x4       x4       x4          x5      
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                                                                      6             
 
                      7 
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1 HIV/HBV/HCV information will be obtained from previous medical history. If the information is not available or a 
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test was performed for > 2 months, then a test will be performed during pre-screening.  
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2 Vancomycin is dosed intraperitoneally in 1-liter of 7.5% icodextrin solution. 
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3 Subjects are ambulatory after study day 1.  
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4 Subjects will have serum creatinine analyzed within the PK sample. 
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5 Laboratory assessments will be ordered at the discretion of the physician-investigator.  
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6 If patient cannot produce urine, a urine drug screen will not be performed. 
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7 If patient cannot produce urine, urinary creatinine and urea will not be performed.  
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Table 1. Summary of study procedures from pre-study to post-study follow-up.  
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Screening Visit for All Subjects (Day -30) 
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Subjects will be screened up to approximately 30 days prior to beginning the study. The screening 
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visit will consist of:  
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 Previous medical history  
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 HIV 
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 Hepatitis B 
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 Hepatitis C 
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 Alcohol and drug screen 
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o If the patient cannot produce urine, then a urine drug screen will not be 
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performed and should not be considered a protocol deviation or exclusionary 
306 
of participation in study  
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 Physical examination  
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 Patient consent  
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 Vital signs 
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 Electrocardiogram (ECG) 
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 Complete blood count 
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 Comprehensive metabolic panel  
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Study Days -1 - 1  
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 Physical exam and vital signs  
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 Urine will be immediately voided prior to dosing  
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 Administer vancomycin 20 mg/kg in 1 liter of 7.5% icodextrin intraperitoneally over 
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approximately 10 to 15 minutes 
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 Off-Cycler Schedule (12 hours) 
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o Blood samples will be obtained during the first 12-hour overnight dwell. A total of two 
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samples will be taken between the time interval following dosing up until hour 12 
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o Vancomycin and serum creatinine will be evaluated from blood samples collected  
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o Dialysate samples will be obtained during the first 12-hour overnight dwell. A total of 
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two samples will be taken between the time interval following dosing up until hour 
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12 
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o Any urine voided will be collected between the time following dosing up until hour 12 
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 If the patient cannot produce urine, then a urine sample will not be possible 
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and should not be considered a protocol deviation  
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 On-Cycler Schedule (9 hours)  
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o Blood will be sampled prior to and after each exchange. Since there are four 
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exchanges, it is anticipated that a total of 8 samples will be obtained during the 9-
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hour on-cycler exchange period 
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o Vancomycin and serum creatinine will be evaluated from blood samples collected  
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o Wasted dialysate from each exchange will be collected and stored 
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o Urine will be collected and pooled  
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 If the patient cannot produce urine, then a urine sample will not be possible 
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and should not be considered a protocol deviation  
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 Discharge from CRU  
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Study Days 2 – 7   
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 An additional 6 blood samples will be taken following study day 1, totaling 1 sample per 
340 
day for the days the patient can come in. A minimum of 4 samples must be collected. If a 
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patient cannot come in for at least 4 of the six days or blood cannot be obtained, it will 
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be considered a protocol deviation. This will be done ideally in the morning, but at a time 
343 
that takes into consideration subject availability and scheduling  
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 Vancomycin and serum creatinine will be evaluated from blood samples collected  
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 Vital signs will be taken  
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 Ambulatory dialysate and 24-hour urine will be collected from the subjects   
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o If the patient cannot produce urine, then a urine sample will not be possible and 
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should not be considered a protocol deviation  
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Post-study follow up  
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The post study visit will include post-study labs (at the investigator or co-investigator’s 
352 
discretion)*, physical exam, vital signs, and adverse event assessment obtained from the end of 
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study.  * As peritoneal dialysis patients come in to clinic regularly and have routine standard of 
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care labs drawn, these may be used to evaluate follow- up safety as long as they are scheduled 
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to be drawn no later than 17 days post dose. 
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4. STUDY POPULATION 
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4.1 
Inclusion Criteria  
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 Adult male or females between 18 – 85 years old  
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 On a PD regimen for > 3 months prior to study initiation  
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4.2 
Exclusion Criteria  
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 Clinically significant disease unrelated to renal impairment or deemed unfit by the 
362 
investigator 
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 Allergy or hypersensitivity to vancomycin or icodextrin-containing dialysis solution  
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 Active peritonitis infection  
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 Hospitalization within < 3 months 
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 Previous intraperitoneal antibiotic treatment within 2 months 
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 Previous intravenous vancomycin treatment within 2 months 
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 Hemoglobin < 9 g/dL  
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 Pregnant or breast-feeding women 
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5. STUDY ENDPOINTS 
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5.1 Primary Pharmacokinetic Endpoint  
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Pharmacokinetic parameters such as the maximum serum concentration (Cmax), time to 
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maximum concentration (Tmax), area under the concentration-time curve (AUC), half-life (t1/2), 
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volume of distribution (VD), dialysate and systemic clearance, and inter-subject variability of 
375 
vancomycin in subjects on APD will be estimated following a non-compartmental analysis (NCA). 
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Dialysate parameters will be estimated following an NCA analysis. Systemic bioavailability from 
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the peritoneal cavity and absorption constant will be estimated. 
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5.2 Secondary Pharmacokinetic Endpoints 
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Residual kidney function as it relates to vancomycin will be assessed based on vancomycin total 
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urinary clearance and cumulative drug excretion. The total dialysate clearance of vancomycin will 
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be explored based on the biological fluids obtained. The safety, tolerability, and stability of 
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vancomycin in 7.5% icodextrin solution will also be described.  
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5.3 Exploratory Pharmacokinetic-Pharmacodynamic Endpoints  
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Parameters generated from the non-compartmental analysis will be used to parameterize the 
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population pharmacokinetic model to explore various dosing profiles. The AUC/MIC ratio will be 
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explored to correlate exposures to the effect of vancomycin in patients on APD.    
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6. MEASUREMENTS AND EVALUATIONS 
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6.1 
Study Data 
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Patient data will be recorded in a secured study database. Elements of interest to the study 
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include:  
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 Patient demographics  
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o Age  
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o Sex 
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o Height 
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o Weight 
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o Race  
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o Cause of ESRD  
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 Laboratory parameters  
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o Serum creatinine (SCr) 
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o Urinary creatinine  
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o Blood Urea Nitrogen (BUN) 
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o Urine urea  
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o Liver function  
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6.2  
Plasma Samples 
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Samples will be processed per laboratory protocol in the laboratory manual. 
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6.3 
Dialysate Samples 
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Samples will be processed per laboratory protocol.  
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6.4 
Urine Samples 
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Samples will be processed per laboratory protocol.  
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7. SAMPLE SIZE AND ANALYSIS PLAN 
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8.1 
Sample Size  
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Due to the exploratory nature of this pharmacokinetic study, no formal sample size calculation 
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was performed. A total of 4 subjects will be enrolled.  
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8.2 
Statistical and Pharmacokinetic Analysis  
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A non-compartmental analysis (NCA) will be utilized to estimate vancomycin pharmacokinetic 
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parameters in patients on APD. The values generated from the NCA will be used to parameterize 
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the population pharmacokinetic model.  
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Data from all patients will be analyzed simultaneously using nonlinear mixed-effects modelling 
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software (NONMEM). A base model will be developed to characterize the data. Covariate analysis 
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will also be evaluated in the model to explain for any intra- and inter-patient PK variability. Model 
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qualification will be validated by using appropriate internal validation procedures based on the 
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data and model development process. 
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8. DATA COLLECTION AND MANAGEMENT PLAN  
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8.1  
Database System Overview 
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Data will be recorded and accessed using Research Electronic Data Capture, known as REDCap. 
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REDCap is a secure web application designed for building and managing database information 
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and meets compliance standards mandated by the Health Insurance Portability and 
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Accountability Act (HIPAA) and FDA 21 CFR Part 11. Data files can be conveniently exported into 
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various data formats (e.g. Microsoft Excel, SAS Statistical Software, R, SPSS, or STATA) for further 
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analysis.  
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8.2 
Case Report Forms and Data Entry 
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Clinical and demographic data will be collected from paper source documents. Information will 
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be entered into an electronic case report form (eCRF). Each enrolled subject’s eCRF will then be 
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transcribed into REDCap and will serve as a central repository of all enrolled subjects in the study. 
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A data monitor will monitor the accuracy of the study charts and data entry. 
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8.3 
Case Report Form Storage and Backup 
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The eCRF will be stored in the Department of Pharmacology & Experimental Therapeutics 
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secured server. Access will only be granted by the principal investigator or co-investigators.  
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9. SAFETY 
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Vancomycin has been previously studied in non-infected patients on peritoneal dialysis. In 
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addition, the dose selected in this study is not devoid of the doses used in previous studies 
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administered intravenously or through the intraperitoneal route.7,9 The safety and tolerability of 
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vancomycin administered through the intraperitoneal route will be assessed in this study by 
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clinical evaluation of vital signs, physical examinations, and laboratory safety evaluations. In 
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addition, continual serum concentration monitoring through blood sampling will be performed 
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as part of this research study. In addition, the likelihood for rare adverse events to vancomycin 
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such as ototoxicity will be unlikely to occur based on the minimal dose used compared to 
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literature.14 Nephrotoxicity from a single IP 20 mg/kg dose of vancomycin would be extremely 
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unlikely in stable, non-septic patients receiving no other potentially nephrotoxic medications or 
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intravenous contrast. Major risk factors for nephrotoxicity related to vancomycin dosing include 
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large daily doses (> 4grams/day), prolonged duration, and concurrent potentially toxic antibiotics 
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(aminoglycosides or piperacillin-tazobactam), none of which apply to this study protocol. Other 
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associated adverse events relating to vancomycin such as anaphylaxis and development of 
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Clostridium difficile infections are considered unlikely.15 In the event that greater than two 
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unexpected and treatment related serious adverse events occur, the study will be halted until 
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review from an independent study monitor is conducted. Cumulative blood draws will be 
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restricted to less than 3 mL per sampling procedure and will be kept in strict accordance with 45 
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CFR 46.402(a) OHRP expedited review categories. Subjects who enrolled in the study will already 
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have hemoglobin levels greater than 9 g/dL eliminating the concern for anemia requiring blood 
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transfusion. 
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