Muhammad Usman and Georg Hempel
Institute of Pharmaceutical and Medicinal Chemistry - Clinical Pharmacy, University of Muenster, Corrensstr. 48, 48149 Muenster, Germany.
Objectives: The aim of this study was to develop a population pharmacokinetic (POPpk) model of meropenem in elderly patients to observe the influence of different covariates on meropenem clearance (CL) and to simulate different dosage regimens in order to observe the percentage probability of target attainment (PTA %) for the plasma concentration of meropenem above MIC of Enterobacteriaceae, Acinetobacter Spp. & Pseudomonas Spp. in relation with renal function.
Methods: The data of patients above 65 years of age treated with meropenem was collected from different sources [1, 2] and consolidated to form a pooled dataset of 178 patients with 493 samples. A POPpk model was developed by using NONMEM® and influence of different covariates on meropenem CL was observed by stepwise covariate modelling. Monte Carlo Simulations of different dosage regimens with daily dose of 3000 mg at steady state were performed to observe the PTA(%) for maintaining the plasma concentration of meropenem above MIC. The targets for T>MIC were 40%, 60% and 80% of dosage intervals using 1000 virtual patients with 5 different levels of CLCR. The simulated dosage regimens were evaluated across the MIC range of 0.25-128 mg/L and the MIC value for which the PTA was ≥ 90% was considered as PK/PD breakpoint.
Results: The data was best described by a two-compartment model with first-order elimination. The values of population parameter estimates for CL, V1, Q and V2 were 5.71 L/h, 14.2 L, 11.8 L/h and 11.2 L respectively. The CLCR and body weight had a significant influence on meropenem CL which is described in final model as CL (L/h) = 5.71×[(1+0.0128)×(CLCR-40.5)×(1+0.0044)×(WT-75)]. The PK/PD breakpoint for 24 h continuous infusion (CI) was 4 mg/L for all the targets of %T>MIC while extended infusions had PK/PD breakpoint one dilution greater than corresponding short infusion regimens for each target of %T>MIC. A 24 h CI was also suitable for maintaining the plasma concentration above MIC of susceptible, intermediate and resistant strains of target bacteria for the entire duration of dosage interval and the levels of CLCR ≥ 100 mL/min.
Conclusions: It is concluded that 3000 mg of meropenem administered over 24 h CI is effective against moderate to severe infections caused by susceptible, intermediate and resistant strains of target bacteria for CLCR level of ≥ 100 mL/min. However, higher dose of meropenem would be required for resistant strains if CLCR is approaching to 200 mL/min.
References:
[1] Doh, K., et al., Population pharmacokinetics of meropenem in burn patients. J Antimicrob Chemother, 2010. 65(11): p. 2428-35.
[2] Isla, A., et al., Population pharmacokinetics of meropenem in critically ill patients undergoing continuous renal replacement therapy. Clin Pharmacokinet, 2008. 47(3): p. 173-80.
Reference: PAGE 25 (2016) Abstr 5703 [www.page-meeting.org/?abstract=5703]
Poster: Drug/Disease modeling - Infection