Ertapenem Pharmacokinetics in Patients in Continuous Ambulatory Peritoneal Dialysis

BACKGROUND:

Infection is a leading cause of morbidity and mortality in end-stage renal disease (ESRD)
patients.[1, 2] Ertapenem is an antibiotic used for the treatment of infections caused by
several organisms, including both Gram positive and negative infections.3 Although
ertapenem pharmacokinetic (PK) parameters have been described in the general population,
this same information for patients on peritoneal dialysis is not available.

Determining optimal antibiotic dosing recommendations for ertapenem is imperative to the
health of CAPD patients in order to prevent either excess medication or sub-therapeutic
doses of the drug. This study will provide clinicians with the necessary information to
safely and effectively treat CAPD patients with ertapenem.

OBJECTIVE The objective of this study is to characterize the pharmacokinetic profile of
ertapenem during continuous ambulatory peritoneal dialysis (CAPD).

RESEARCH DESIGN & METHODS:

Study Location This study will be conducted at an outpatient dialysis clinic (Hortense and
Louis Rubin Dialysis Center, Clifton Park, NY), where all blood, dialysate, and urine
sampling will occur.

Study Population To accomplish the study objective, a prospective, open-label,
pharmacokinetic study of ertapenem in 8 patients on CAPD will be conducted. The desired
composition of the study population will consist of approximately 4 males and 4 females, 6
of whom will be Caucasian, and 2 non-Caucasian patients. This patient composition was
selected because it reflects the demographic at the Hortense and Louis Rubin Dialysis
Center, Clifton Park, NY.

i. Inclusion criteria Adult patients (≥ 18 years), non-infected (afebrile, lack of
constitutional symptoms and no leukocytosis), on a stable PD regimen (at least one month)
are eligible for participation. Both patients with and without residual renal function will
be studied. Non-anuric patients concurrently receiving medications with the potential to
inhibit active tubular secretion will be allowed to enter the study after a 2-week washout
period. These medications include H2-antagonists, trimethoprim, or probenecid. The patient
and their physician at the Hortense and Louis Rubin Dialysis Center will contacted if any
medication needs to be discontinued.

ii. Exclusion criteria Patients will be ineligible for the study if they have had
peritonitis within the previous 4 weeks, clinical signs or symptoms of active infection,
elevated white blood cell count, or treatment with any antibiotic within the previous 2
weeks. Patients with a hemoglobin (hgb) < 11 g/dL will be ineligible for study inclusion.
Patients with stated or documented allergies to beta-lactams medications will not be
eligible. Pregnant or breastfeeding women will not be eligible for inclusion. All women of
child-bearing age will need to yield a serum hCG ≤ 5 mIU/mL within 2 weeks of the scheduled
study day. Patients taking valproic acid will also be excluded.

Research Plan Prior to the initiation of the study protocol, informed consent will be
obtained from each participant. A translator will be consulted to accommodate non-English
speaking study patients.

i. Dialysis Prescription Eligible patients will receive a standardized CAPD prescription
of 4 daily exchanges with 2 L of 2.5% dextrose dialysate, having dwell periods of 6 hours, 4
hours, 6 hours and 8 hours, respectively, starting 7 days prior to ertapenem administration
day. On the study day, patients will perform 2 exchanges at the Hortense and Louis Rubin
Dialysis Center.

ii. Pre-Ertapenem Administration Procedure Two weeks prior to the study day, all women
of child-bearing age will be required to yield a negative pregnancy test (hCG ≤ 5 mIU/mL).

One week prior to the study day, a complete blood count (CBC) will be checked to ensure that
the Hb concentration is ≥11 g/dL and white blood cell (WBC) count is normal (5-10,000
cells/mm3). The patients' weights will also be recorded at this time.

On the study day, patients will arrive at the dialysis clinic, drain their peritoneal cavity
and instill fresh dialysate by way of the PD catheter over 5 - 10 minutes using a Y-type
administration set. Spent dialysate from the preceding exchange will be drained immediately
prior to the intravenous injection of ertapenem. Patients with residual renal function will
urinate immediately prior to administration of ertapenem. An aliquot (10 mL) of urine will
be saved and tested to ensure that no interfering substances are present that would
invalidate the assay used for ertapenem determination in the urine.

Patients will have two peripheral venous catheters placed: 1) for drug administration and 2)
for blood sampling purposes.

iii. Ertapenem Administration On the study day, subjects will be given ertapenem 500 mg IV
over a 30 minute infusion.

iv. Blood and Dialysate Sampling Patients will perform 2 CAPD exchanges during the study
period, during which 13 blood samples and 13 dialysate samples will be collected (see
figure).

v. Urine Collection Non-anuric patients will be required to collect their urine during the
course of the study period.

vi. Sample preparation and assay methods The urine, plasma, and dialysate concentrations of
ertapenem will be determined by a high pressure liquid chromatography (HPLC) or a liquid
chromatography / mass spectrometry (LCMS) device. Blood samples will be collected in
standard blood collection tubes containing sodium heparin having a maximum volume of 4 mL.
Samples will be stored on ice until the plasma is harvested (within 2 hours). Plasma will
be obtained by placing the blood samples in a centrifuge at room temperature at
approximately 3000 - 4000 rpm for 15 minutes. The plasma will then be withdrawn, split into
2 aliquots of equal volume, and transferred into separate polypropylene tubes (Tube 1, Tube
2). The tubes are pre-labeled as either Set A (Tube 1) or Set B (Tube 2). The labels will
be in indelible ink. The following information will be included on the labels: sample type
(plasma), dose number after which the sample was collected (i.e., dose #3), protocol number,
subject number, date and time of sampling.

Similarly the dialysate and urine samples will be split into two batches and stored at -20oC
until assayed. The dialysate will be mixed thoroughly. The total sample volume will be
recorded. Two milliliters of dialysate will be transferred into each of the polypropylene
tubes (Tube 1 and Tube 2). The tubes are pre-labeled as either Set A (Tube 1) or Set B
(Tube 2). The labels will be in indelible ink. The following information will be included
on the labels: sample type (dialysate), dose number after which the sample was collected
(i.e., dose #3), protocol number, subject number, date and time of sampling. Samples will
be stored frozen at -20 degrees Centigrade until they are shipped for concentration
determination. Blank dialysate (without ertapenem in it) will also be sent for assay to
assess for potential interfering substances in the assay and to serve as analytical controls
for the assay. The blank dialysate samples will be 10-20 mL stored in individual
polypropylene tubes, clearly marked, "dialysis blank." On a separate piece of paper, the
specific concentration of each component of the dialysate fluid (i.e., electrolytes,
dextrose, saline, etc.) will be included in the shipment.

Urine will be collected and split into two aliquots of equal volume and transferred to
polypropylene tubes (Tube 1 and Tube 2). The tubes will pre-labeled as Tube A (Tube 1) and
Tube B (Tube 2). Tubes will be pre-labeled with indelible ink and include the following
information: sample type (urine), protocol number, and subject number. Samples will be
stored frozen at -20 degrees Centigrade until they are shipped for ertapenem concentration
determination.

One batch of dialysate samples will be packed on dry ice (sufficient for 2 days) and shipped
to a location to be determined by Merck. One batch of blood and urine samples will be
packed in dry ice (sufficient for 2 days) and shipped to a location to be determined by
Merck. The second batch of samples (dialysate, blood, and urine) will be sent to a central
laboratory (Quest Diagnostics, Inc) for serum, urine, and dialysate creatinine and urea
assay and dialysate dextrose concentration assay.

Data Analysis:

All pharmacokinetic data will be analyzed in a population pharmacokinetic model using the
Non Parametric Adaptive Grid with adaptive γ (NPAG) program of Leary, Schumitzky and
Jelliffe.5 Upon obtaining model convergence, the mean parameter vector and covariance
matrix from the population pharmacokinetic analysis will be embedded in Subroutine Prior of
the ADAPT II package of programs of D'Argenio and Schumitzky.6 The population simulation
without process noise option will be employed. A 9,999 subject Monte Carlo simulation will
be performed to examine an array of potential ertapenem candidate dosing regimens in CAPD.

REFERENCES

1. Bloembergen WE, Port FK. Epidemiological perspective on infections in chronic dialysis
patients. Adv Ren Replace Ther. Jul 1996;3(3):201-207.

2. United States Renal Data System. USRDS Annual Data Report: Atlas of End-stage Renal
Disease in the United States. Bethesda, MD: National Institute of Health, National
Institute of Diabetes and Digestive and Kidney Diseases; 2007.

3. Merck & Co, Inc. Invanz (ertapenem) package insert. Whitehouse Station, NJ; 2008.

4. D'Argenio DZ, Schumitzky A. A program package for simulation and parameter estimation
in pharmacokinetic systems. Comput Programs Biomed. Mar 1979;9(2):115-134.

5. Leary, R., R. Jelliffe, A. Schumitzky, and M. van Guilder. An adaptive grid,
non-parametric approach to pharmacokinetic and dynamic (PK/PD) models. Proceedings,
Fourteenth IEEE Symposium on Computer-Based Medical Systems. 26-27 July 2001. Bethesda,
MD, IEEE Computer Society, pp. 389-394.

6. D'Argenio, D. Z., and A. Schumitzky. 1979. A program package for simulation and
parameter estimation in pharmacokinetic systems. Comput Programs Biomed 9:115-34.