Clinical trial NCT03685747
Conditions: Peritoneal Dialysis-associated Peritonitis
Keywords: Vancomycin Pharmacokinetics Pharmacodynamics Automated Peritoneal Dialysis
Sponsor: Thomas Jefferson University
Start date: 2018-11-15; Completion date: 2020-10-01
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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 documents:
Prot_SAP_000.pdf: 
Pharmacokinetics of Vancomycin in Automated Peritoneal Dialysis  
PROTOCOL 
Page 1 of 14 
 
 
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 
 
4 
 
5 
 
6 
 
7 
 
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 


Pharmacokinetics of Vancomycin in Automated Peritoneal Dialysis  
PROTOCOL 
Page 2 of 14 
 
Table of Contents 
12 
 
13 
 
14 
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 
38 
 
39 
 
40 
 
41 
 
42 
 
43 
 
44 
 
45 


Pharmacokinetics of Vancomycin in Automated Peritoneal Dialysis  
PROTOCOL 
Page 3 of 14 
 
1. INTRODUCTION 
46 
Peritoneal dialysis (PD) is a form of renal replacement therapy indicated for those with acute 
47 
kidney injury or end stage renal disease (ESRD). In 2013 PD was utilized in approximately 7% of 
48 
the 660,000 prevalent patients with ESRD in the United States. Within that time, the prevalence 
49 
of PD has seen an increase by over 30% between 2007 – 2014.1 During PD, a hyperosmolar 
50 
solution is introduced into the peritoneal cavity allowing solute exchange between the dialysate-
51 
contained in the cavity and blood from the perfused peritoneum. A concentration gradient is thus 
52 
created allowing ultrafiltration and diffusional clearance of toxic materials. PD fluids are available 
53 
as glucose-based or non-glucose based solutions. Commonly prescribed glucose-based PD 
54 
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 
56 
based solution marketed in the United States have shown to improve fluid removal during long 
57 
dialysis exchanges and offer greater peritoneal membrane protection.2   
58 
 
59 
Principles of Peritoneal Dialysis 
60 
Currently, two modalities of PD exist and is individualized based on patient and life-style specific 
61 
factors. Continuous ambulatory peritoneal dialysis (CAPD) allows 4 – 5 exchanges performed 
62 
manually whereas automated peritoneal dialysis (APD) involves continuous, automated, cyclical 
63 
exchanges performed by a device at home during the night.3 APD offers advantages over CAPD 
64 
by allowing fluid-free or “dry” daytime dwells thereby permitting those who require PD liberty 
65 
for their activities of daily living. In addition, several other advantages such as lower incidences 
66 
of infection and hernias, enhanced solute clearances, and positive psychosocial impact have been 
67 
reported.3 Overall, the prevalence of APD has been increasing throughout the years as the 
68 
number of patients utilizing CAPD declines.4  
69 
 
70 
Vancomycin in Peritoneal Dialysis  
71 
Peritonitis is a common complication in PD and accounts for a large portion of hospital 
72 
readmission and mortality.1,5 In addition, severe or prolonged peritonitis can lead to membrane 
73 
failure prompting the switch from PD to hemodialysis. The International Society of Peritoneal 
74 
Dialysis (ISPD) recommends intraperitoneal administration as the preferred route to deliver 
75 
antibiotics in the absence of systemic bacteremia.5 Vancomycin is the most common antibiotic 
76 
recommended and has notable gram-positive coverage used empirically during suspected 
77 
peritonitis.   
78 
Rationale for the Proposed Study  
79 
Vancomycin is eliminated unchanged in the urine through glomerular filtration and is best 
80 
characterized by a distribution and elimination phase following parenteral administration. 
81 
Vancomycin’s bactericidal activity is considered time-dependent with the ratio of the 24-hour 
82 
area-under-the-concentration (AUC) versus time/minimal-inhibitory concentration (MIC) ratio 
83 
(AUC/MIC) being the best pharmacokinetic/pharmacodynamic predictor of effectiveness. The 
84 
preferred AUC/MIC ratio is > 400. Dosing in the range of 15-30 mg/kg is recommended by several 
85 


Pharmacokinetics of Vancomycin in Automated Peritoneal Dialysis  
PROTOCOL 
Page 4 of 14 
 
professional societies including ISPD to maintain a serum concentration level of 15 mg/L in order 
86 
to maximize efficacy and reduce toxicity, although this trough is only loosely correlated with 
87 
corresponding AUC/MIC.5,6 Furthermore, the evidence supporting this recommended trough is 
88 
essentially nonexistent in PD patients on APD, where data on vancomycin bioavailability and 
89 
clearance with varying degrees of peritoneal function is sparse. In addition, early 
90 
pharmacokinetic studies were conducted only in patients on CAPD modalities, glucose-based 
91 
prescriptions, or those on intravenous vancomycin.7-9  Lastly, the relationship between serum 
92 
concentration and site of action at the peritoneal cavity wall is not established. In totality, the 
93 
goal is to close the knowledge gap in this very common use of vancomycin.  
94 
Although the ISPD advisory committee on peritonitis management recommends a 25% increase 
95 
in antibiotic dose in non-anuric patients, residual kidney function may affect the exposure, 
96 
clearance, distribution and serum half-life for those antibiotics administered. This however is an 
97 
empiric recommendation and there is no formal quantification of how residual kidney function 
98 
(RKF) may impact pharmacokinetics. The impact on RKF on vancomycin in PD is also lacking. RKF 
99 
is critical for the welfare and survival of PD patients. Indeed, 2 large multicenter studies, the 
100 
Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD-2) (AJKD;41:1293-2302, 
101 
2003) and the Canada/USA Peritoneal Adequacy Study (CANUSA) (JASN, 12:2158-2162, 2001), 
102 
both have shown statistically significant (by multivariable analyses) 12% reductions in mortality 
103 
per ml/min/1.73 m2 residual GFR increase or per 5L/week residual GFR increase, respectively.  
104 
Hence, it is important to assess vancomycin pharmacokinetics in PD patients with RKF for two 
105 
reasons. First, the enhanced vancomycin clearance of RKF may result in under-dosing and 
106 
secondly, overdosing may result in nephrotoxicity and loss of critically important RKF. This 
107 
presents a challenge when considering the bi-exponential pharmacokinetic behavior of 
108 
vancomycin and produces a significant source of variability allowing controversy in the role of 
109 
monitoring serum vancomycin in patients on APD.10,11 
110 
Interestingly, a recent retrospective analysis examining residual renal function and peritonitis 
111 
outcomes show that the odds of peritonitis treatment failure for those with urinary creatinine 
112 
clearances of greater than 5 mL/min were greater when compared to those who were anuric.12 
113 
These associations further challenge the need for optimal vancomycin dosing strategies in 
114 
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 
117 
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 
119 
icodextrin marketed in the United States have shown to improve fluid removal during long 
120 
dialysis exchanges and offer greater peritoneal membrane protection.  In-vitro studies conducted 
121 
with 7.5% icodextrin demonstrate physical compatibility and chemical stability, however there is 
122 
a lack of information for the clearance, stability and effect on the minimum inhibitory 
123 


Pharmacokinetics of Vancomycin in Automated Peritoneal Dialysis  
PROTOCOL 
Page 5 of 14 
 
concentration of vancomycin in-vivo.13 As there will be increasing use of icodextrin, 
124 
characterization of vancomycin pharmacokinetics will be important. 
125 
Therefore, this current study aims to explore the pharmacokinetics and pharmacodynamics of 
126 
intraperitoneal administered vancomycin in un-infected subjects on APD and explore the in-vivo 
127 
behavior of vancomycin in 7.5% icodextrin PD solution.    
128 
2. STUDY OBJECTIVES 
129 
2.1 
Primary Objective  
130 
 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 
139 
 Investigate dosing recommendations and adjustments based on population 
140 
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). 
153 
 
154 
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.  
159 
 
160 
 
161 


Pharmacokinetics of Vancomycin in Automated Peritoneal Dialysis  
PROTOCOL 
Page 6 of 14 
 
 
162 
 
163 
 
164 
 
165 
 
166 
 
167 
 
168 
 
169 
 
170 
 
171 
 
172 
 
173 
 
174 
 
175 
 
176 
Figure 1. Schematic depiction of APD regimen.  
177 
 
178 
 
179 
 
180 
 
181 
 
182 
 
183 
 
184 
 
185 
 
186 
 
187 
 
188 
 
189 
 
190 
 
191 
 
192 
 
193 
 
194 
 
195 
 
196 
 
197 
 
198 
 
199 
 
200 
 
201 
 
202 
 
203 
 
204 
 
205 


Pharmacokinetics of Vancomycin in Automated Peritoneal Dialysis  
PROTOCOL 
Page 7 of 14 
 
 
206 
3.2 
Schedule & Procedures 
207 
A schematic is illustrated in figure 2 and study procedure detailed in table 1.   
208 
 
209 
 
210 
 
211 
 
212 
 
213 
 
214 
 
215 
 
216 
 
217 
 
218 
 
219 
 
220 
 
221 
 
222 
 
223 
 
224 
 
225 
 
226 
 
227 
 
228 
 
229 
 
230 
 
231 
 
232 
 
233 
 
234 
 
235 
 
236 
 
237 
 
238 
 
239 
 
240 
 
241 
 
242 
 
243 
 
244 
 
245 
 
246 
 
247 
Figure 2. Study day and sampling schematic 
248 


Pharmacokinetics of Vancomycin in Automated Peritoneal Dialysis  
PROTOCOL 
Page 8 of 14 
 
 
249 
 
250 
 
251 
 
252 
 
253 
 
254 
 
255 
 
256 
 
257 
 
258 
 
 
 
 
 
 
 
 
 
              x5   
259 
 
260 
 
 
 
 
 
      x4           x4     x4       x4      x4       x4       x4          x5      
261 
 
262 
                                                                      6             
 
                      7 
263 
 
264 
 
265 
 
266 
 
267 
 
268 
 
269 
 
270 
 
271 
 
272 
 
273 
 
274 
 
275 
 
276 
 
277 
 
278 
 
279 
 
280 
 
281 
 
282 
 
283 
 
284 
1 HIV/HBV/HCV information will be obtained from previous medical history. If the information is not available or a 
285 
test was performed for > 2 months, then a test will be performed during pre-screening.  
286 
2 Vancomycin is dosed intraperitoneally in 1-liter of 7.5% icodextrin solution. 
287 
3 Subjects are ambulatory after study day 1.  
288 
4 Subjects will have serum creatinine analyzed within the PK sample. 
289 
5 Laboratory assessments will be ordered at the discretion of the physician-investigator.  
290 
6 If patient cannot produce urine, a urine drug screen will not be performed. 
291 
7 If patient cannot produce urine, urinary creatinine and urea will not be performed.  
292 
 
293 
Table 1. Summary of study procedures from pre-study to post-study follow-up.  
294 
 
295 
 
296 


Pharmacokinetics of Vancomycin in Automated Peritoneal Dialysis  
PROTOCOL 
Page 9 of 14 
 
Screening Visit for All Subjects (Day -30) 
297 
Subjects will be screened up to approximately 30 days prior to beginning the study. The screening 
298 
visit will consist of:  
299 
 Previous medical history  
300 
 HIV 
301 
 Hepatitis B 
302 
 Hepatitis C 
303 
 Alcohol and drug screen 
304 
o If the patient cannot produce urine, then a urine drug screen will not be 
305 
performed and should not be considered a protocol deviation or exclusionary 
306 
of participation in study  
307 
 Physical examination  
308 
 Patient consent  
309 
 Vital signs 
310 
 Electrocardiogram (ECG) 
311 
 Complete blood count 
312 
 Comprehensive metabolic panel  
313 
Study Days -1 - 1  
314 
 Physical exam and vital signs  
315 
 Urine will be immediately voided prior to dosing  
316 
 Administer vancomycin 20 mg/kg in 1 liter of 7.5% icodextrin intraperitoneally over 
317 
approximately 10 to 15 minutes 
318 
 Off-Cycler Schedule (12 hours) 
319 
o Blood samples will be obtained during the first 12-hour overnight dwell. A total of two 
320 
samples will be taken between the time interval following dosing up until hour 12 
321 
o Vancomycin and serum creatinine will be evaluated from blood samples collected  
322 
o Dialysate samples will be obtained during the first 12-hour overnight dwell. A total of 
323 
two samples will be taken between the time interval following dosing up until hour 
324 
12 
325 
o Any urine voided will be collected between the time following dosing up until hour 12 
326 
 If the patient cannot produce urine, then a urine sample will not be possible 
327 
and should not be considered a protocol deviation  
328 
 On-Cycler Schedule (9 hours)  
329 
o Blood will be sampled prior to and after each exchange. Since there are four 
330 
exchanges, it is anticipated that a total of 8 samples will be obtained during the 9-
331 
hour on-cycler exchange period 
332 
o Vancomycin and serum creatinine will be evaluated from blood samples collected  
333 
o Wasted dialysate from each exchange will be collected and stored 
334 
o Urine will be collected and pooled  
335 
 If the patient cannot produce urine, then a urine sample will not be possible 
336 
and should not be considered a protocol deviation  
337 
 Discharge from CRU  
338 


Pharmacokinetics of Vancomycin in Automated Peritoneal Dialysis  
PROTOCOL 
Page 10 of 14 
 
Study Days 2 – 7   
339 
 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 
341 
patient cannot come in for at least 4 of the six days or blood cannot be obtained, it will 
342 
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  
344 
 Vancomycin and serum creatinine will be evaluated from blood samples collected  
345 
 Vital signs will be taken  
346 
 Ambulatory dialysate and 24-hour urine will be collected from the subjects   
347 
o If the patient cannot produce urine, then a urine sample will not be possible and 
348 
should not be considered a protocol deviation  
349 
 
350 
Post-study follow up  
351 
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 
353 
study.  * As peritoneal dialysis patients come in to clinic regularly and have routine standard of 
354 
care labs drawn, these may be used to evaluate follow- up safety as long as they are scheduled 
355 
to be drawn no later than 17 days post dose. 
356 
4. STUDY POPULATION 
357 
4.1 
Inclusion Criteria  
358 
 Adult male or females between 18 – 85 years old  
359 
 On a PD regimen for > 3 months prior to study initiation  
360 
4.2 
Exclusion Criteria  
361 
 Clinically significant disease unrelated to renal impairment or deemed unfit by the 
362 
investigator 
363 
 Allergy or hypersensitivity to vancomycin or icodextrin-containing dialysis solution  
364 
 Active peritonitis infection  
365 
 Hospitalization within < 3 months 
366 
 Previous intraperitoneal antibiotic treatment within 2 months 
367 
 Previous intravenous vancomycin treatment within 2 months 
368 
 Hemoglobin < 9 g/dL  
369 
 Pregnant or breast-feeding women 
370 
5. STUDY ENDPOINTS 
371 
5.1 Primary Pharmacokinetic Endpoint  
372 
Pharmacokinetic parameters such as the maximum serum concentration (Cmax), time to 
373 
maximum concentration (Tmax), area under the concentration-time curve (AUC), half-life (t1/2), 
374 
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). 
376 


Pharmacokinetics of Vancomycin in Automated Peritoneal Dialysis  
PROTOCOL 
Page 11 of 14 
 
Dialysate parameters will be estimated following an NCA analysis. Systemic bioavailability from 
377 
the peritoneal cavity and absorption constant will be estimated. 
378 
 
379 
5.2 Secondary Pharmacokinetic Endpoints 
380 
Residual kidney function as it relates to vancomycin will be assessed based on vancomycin total 
381 
urinary clearance and cumulative drug excretion. The total dialysate clearance of vancomycin will 
382 
be explored based on the biological fluids obtained. The safety, tolerability, and stability of 
383 
vancomycin in 7.5% icodextrin solution will also be described.  
384 
 
385 
5.3 Exploratory Pharmacokinetic-Pharmacodynamic Endpoints  
386 
Parameters generated from the non-compartmental analysis will be used to parameterize the 
387 
population pharmacokinetic model to explore various dosing profiles. The AUC/MIC ratio will be 
388 
explored to correlate exposures to the effect of vancomycin in patients on APD.    
389 
 
390 
6. MEASUREMENTS AND EVALUATIONS 
391 
6.1 
Study Data 
392 
Patient data will be recorded in a secured study database. Elements of interest to the study 
393 
include:  
394 
 Patient demographics  
395 
o Age  
396 
o Sex 
397 
o Height 
398 
o Weight 
399 
o Race  
400 
o Cause of ESRD  
401 
 Laboratory parameters  
402 
o Serum creatinine (SCr) 
403 
o Urinary creatinine  
404 
o Blood Urea Nitrogen (BUN) 
405 
o Urine urea  
406 
o Liver function  
407 
6.2  
Plasma Samples 
408 
Samples will be processed per laboratory protocol in the laboratory manual. 
409 
6.3 
Dialysate Samples 
410 
Samples will be processed per laboratory protocol.  
411 
6.4 
Urine Samples 
412 
Samples will be processed per laboratory protocol.  
413 


Pharmacokinetics of Vancomycin in Automated Peritoneal Dialysis  
PROTOCOL 
Page 12 of 14 
 
7. SAMPLE SIZE AND ANALYSIS PLAN 
414 
8.1 
Sample Size  
415 
Due to the exploratory nature of this pharmacokinetic study, no formal sample size calculation 
416 
was performed. A total of 4 subjects will be enrolled.  
417 
8.2 
Statistical and Pharmacokinetic Analysis  
418 
A non-compartmental analysis (NCA) will be utilized to estimate vancomycin pharmacokinetic 
419 
parameters in patients on APD. The values generated from the NCA will be used to parameterize 
420 
the population pharmacokinetic model.  
421 
 
422 
Data from all patients will be analyzed simultaneously using nonlinear mixed-effects modelling 
423 
software (NONMEM). A base model will be developed to characterize the data. Covariate analysis 
424 
will also be evaluated in the model to explain for any intra- and inter-patient PK variability. Model 
425 
qualification will be validated by using appropriate internal validation procedures based on the 
426 
data and model development process. 
427 
8. DATA COLLECTION AND MANAGEMENT PLAN  
428 
8.1  
Database System Overview 
429 
Data will be recorded and accessed using Research Electronic Data Capture, known as REDCap. 
430 
REDCap is a secure web application designed for building and managing database information 
431 
and meets compliance standards mandated by the Health Insurance Portability and 
432 
Accountability Act (HIPAA) and FDA 21 CFR Part 11. Data files can be conveniently exported into 
433 
various data formats (e.g. Microsoft Excel, SAS Statistical Software, R, SPSS, or STATA) for further 
434 
analysis.  
435 
8.2 
Case Report Forms and Data Entry 
436 
Clinical and demographic data will be collected from paper source documents. Information will 
437 
be entered into an electronic case report form (eCRF). Each enrolled subject’s eCRF will then be 
438 
transcribed into REDCap and will serve as a central repository of all enrolled subjects in the study. 
439 
A data monitor will monitor the accuracy of the study charts and data entry. 
440 
8.3 
Case Report Form Storage and Backup 
441 
The eCRF will be stored in the Department of Pharmacology & Experimental Therapeutics 
442 
secured server. Access will only be granted by the principal investigator or co-investigators.  
443 
9. SAFETY 
444 
Vancomycin has been previously studied in non-infected patients on peritoneal dialysis. In 
445 
addition, the dose selected in this study is not devoid of the doses used in previous studies 
446 
administered intravenously or through the intraperitoneal route.7,9 The safety and tolerability of 
447 
vancomycin administered through the intraperitoneal route will be assessed in this study by 
448 
clinical evaluation of vital signs, physical examinations, and laboratory safety evaluations. In 
449 
addition, continual serum concentration monitoring through blood sampling will be performed 
450 


Pharmacokinetics of Vancomycin in Automated Peritoneal Dialysis  
PROTOCOL 
Page 13 of 14 
 
as part of this research study. In addition, the likelihood for rare adverse events to vancomycin 
451 
such as ototoxicity will be unlikely to occur based on the minimal dose used compared to 
452 
literature.14 Nephrotoxicity from a single IP 20 mg/kg dose of vancomycin would be extremely 
453 
unlikely in stable, non-septic patients receiving no other potentially nephrotoxic medications or 
454 
intravenous contrast. Major risk factors for nephrotoxicity related to vancomycin dosing include 
455 
large daily doses (> 4grams/day), prolonged duration, and concurrent potentially toxic antibiotics 
456 
(aminoglycosides or piperacillin-tazobactam), none of which apply to this study protocol. Other 
457 
associated adverse events relating to vancomycin such as anaphylaxis and development of 
458 
Clostridium difficile infections are considered unlikely.15 In the event that greater than two 
459 
unexpected and treatment related serious adverse events occur, the study will be halted until 
460 
review from an independent study monitor is conducted. Cumulative blood draws will be 
461 
restricted to less than 3 mL per sampling procedure and will be kept in strict accordance with 45 
462 
CFR 46.402(a) OHRP expedited review categories. Subjects who enrolled in the study will already 
463 
have hemoglobin levels greater than 9 g/dL eliminating the concern for anemia requiring blood 
464 
transfusion. 
465 
10. REFERENCES 
466 
1. 
Chan L, Poojary P, Saha A, et al. Reasons for admission and predictors of national 30-day 
467 
readmission rates in patients with end-stage renal disease on peritoneal dialysis. Clin Kidney J. 
468 
2017;10(4):552-559. 
469 
2. 
Garcia-Lopez E, Lindholm B, Davies S. An update on peritoneal dialysis solutions. Nat Rev 
470 
Nephrol. 2012;8(4):224-233. 
471 
3. 
Rabindranath KS, Adams J, Ali TZ, Daly C, Vale L, Macleod AM. Automated vs continuous 
472 
ambulatory peritoneal dialysis: a systematic review of randomized controlled trials. Nephrol Dial 
473 
Transplant. 2007;22(10):2991-2998. 
474 
4. 
Manley HJ, Bailie GR. Treatment of peritonitis in APD: pharmacokinetic principles. Semin Dial. 
475 
2002;15(6):418-421. 
476 
5. 
Li PK, Szeto CC, Piraino B, et al. ISPD Peritonitis Recommendations: 2016 Update on Prevention 
477 
and Treatment. Perit Dial Int. 2016;36(5):481-508. 
478 
6. 
Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult 
479 
patients: a consensus review of the American Society of Health-System Pharmacists, the 
480 
Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J 
481 
Health Syst Pharm. 2009;66(1):82-98. 
482 
7. 
Morse GD, Farolino DF, Apicella MA, Walshe JJ. Comparative study of intraperitoneal and 
483 
intravenous vancomycin pharmacokinetics during continuous ambulatory peritoneal dialysis. 
484 
Antimicrob Agents Chemother. 1987;31(2):173-177. 
485 
8. 
Bunke CM, Aronoff GR, Brier ME, Sloan RS, Luft FC. Vancomycin kinetics during continuous 
486 
ambulatory peritoneal dialysis. Clin Pharmacol Ther. 1983;34(5):631-637. 
487 
9. 
Manley HJ, Bailie GR, Frye RF, McGoldrick MD. Intravenous vancomycin pharmacokinetics in 
488 
automated peritoneal dialysis patients. Perit Dial Int. 2001;21(4):378-385. 
489 
10. 
Fish R, Nipah R, Jones C, Finney H, Fan SL. Intraperitoneal vancomycin concentrations during 
490 
peritoneal dialysis-associated peritonitis: correlation with serum levels. Perit Dial Int. 
491 
2012;32(3):332-338. 
492 
11. 
Stevenson S, Tang W, Cho Y, et al. The role of monitoring vancomycin levels in patients with 
493 
peritoneal dialysis-associated peritonitis. Perit Dial Int. 2015;35(2):222-228. 
494 


Pharmacokinetics of Vancomycin in Automated Peritoneal Dialysis  
PROTOCOL 
Page 14 of 14 
 
12. 
Whitty R, Bargman JM, Kiss A, Dresser L, Lui P. Residual Kidney Function and Peritoneal Dialysis-
495 
Associated Peritonitis Treatment Outcomes. Clin J Am Soc Nephrol. 2017;12(12):2016-2022. 
496 
13. 
Ranganathan D, Naicker S, Wallis SC, Lipman J, Ratanjee SK, Roberts JA. Stability of Antibiotics 
497 
for Intraperitoneal Administration in Extraneal 7.5% Icodextrin Peritoneal Dialysis Bags (STAB 
498 
Study). Perit Dial Int. 2016;36(4):421-426. 
499 
14. 
Tokgoz B, Somdas MA, Ucar C, et al. Correlation between hearing loss and peritonitis frequency 
500 
and administration of ototoxic intraperitoneal antibiotics in patients with CAPD. Ren Fail. 
501 
2010;32(2):179-184. 
502 
15. 
Sun Y, Huskey RL, Tang L, et al. Adverse effects of intravenous vancomycin-based prophylaxis 
503 
during therapy for pediatric acute myeloid leukemia. Antimicrob Agents Chemother. 2017. 
504 
 
505