Sami Ullaha (1)#, Martin Ursli (2), Uwe Fuhr (1), Martin Wiesholzer (2), Manuel Kussmann (3), Wolfgang Poeppl (3,5), Markus Zeitlinger (4), Max Taubert (1)
1) University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Pharmacology, Department I of Pharmacology, Cologne, Germany (2) Department of Internal Medicine I, University Hospital St. Poelten, Karl Landsteiner University of Health Sciences, St. Poelten, Austria (3,4) Department of Internal Medicine I and Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria (5) Department of Dermatology and Tropical Medicine, Military Medical Cluster East, Austrian Armed Forces, Vienna, Austria
Objectives: Peritonitis is a serious complication of peritoneal dialysis (PD). In general, intraperitoneal (i.p.) application of antimicrobial agents is known to be superior to the intravenous (i.v.) administration in peritonitis patients. Meropenem is recommended as a second line agent for the treatment of peritonitis involving Pseudomonas species. However, the dosing of meropenem is unclear in peritonitis patients undergoing automated peritoneal dialysis (APD). Previous data has suggested that 1 g daily i.p. dose is effective in treating peritonitis in continuous ambulatory peritoneal dialysis (CAPD) patients1. However, the authors of this study have speculated that a lower dose might also be sufficient in PD patients and it is not certain whether there is any risk of accumulation with this dose. Therefore, the objective of this study was to assess the probability of target attainment (PTA) of meropenem in APD patients based on population pharmacokinetic modeling and Monte Carlo simulations.
Methods: This evaluation was performed based on a data from a randomized, crossover pharmacokinetic study conducted in six APD patients without peritonitis2. Plasma and dialysate concentrations were determined by high-performance liquid chromatography tandem mass spectroscopy (HPLC-MS) after administration of a single dose of 500 mg i.v. or i.p. meropenem (total 360 samples). A non-linear mixed effects model was developed for plasma and dialysate concentrations using NONMEM 7.4.3. Based on the population pharmacokinetic model, Monte Carlo simulations were performed using 3000 virtual subjects to determine the optimum i.v. and i.p dose required. T>MIC ≥ 40% (fraction of a dosing interval during which free meropenem concentrations exceeded the minimum inhibitory concentration [MIC]) was defined as the PK/PD target against clinically relevant pathogens (MIC of 2 mg/L for Pseudomonas aeruginosa and 8 mg/L for less susceptible pathogens).
Results: A two-compartment model with linear elimination described the plasma concentrations well. Similarly, a two-compartment model was needed for the dialysate concentrations with transfer between the peripheral plasma compartment and the central dialysate compartment. The goodness of fit plots and visual predictive checks showed that the model had reasonably described both the plasma and dialysate fluid data. For an MIC of 2 mg/L, the PTA in plasma and dialysate after a single 500 mg i.v. dose was 100 and 78% respectively. An i.v. dose of 750 mg was needed to achieve the target in more than 90% of the patients in dialysate. On the other hand, an i.p. dose of 250 mg was sufficient to attain a PTA of more than 90% in plasma and dialysate. For an MIC of 8 mg/L, an i.v. dose of 2500 mg was required to attain more than 90% PTA in plasma and dialysate, as compared to only 750 mg of i.p. dose. According to our model, no relevant accumulation of meropenem in plasma and/or peritoneal fluid is expected for long-term treatment with i.p. 750 mg daily.
Conclusions: An i.p. dose of 750 mg per day is optimal for pathogens with an MIC ≤ 8mg/L with no risk of accumulation in APD patients.
References:
[1] Vlaar, P. J., Hulst, M. van, Benne, C. A. & Janssen, W. M. Intraperitoneal compared with intravenous meropenem for peritoneal dialysis-related peritonitis. Perit. Dial. Int. 33, 708–709 (2013).
[2] Wiesholzer, M. et al. An open, randomized, single-center, crossover pharmacokinetic study of meropenem after intraperitoneal and intravenous administration in patients receiving automated peritoneal dialysis. Antimicrob. Agents Chemother. 60, 2790–2797 (2016).
Reference: PAGE 29 (2021) Abstr 9860 [www.page-meeting.org/?abstract=9860]
Poster: Clinical Applications