Humanizing meropenem dosage regimens by co-administration of cilastatin in an immunocompetent mouse bloodstream infection model of Acinetobacter baumannii based on a novel quantitative matching framework.

Abstract

Background: Meropenem is commonly used to treat serious bacterial infections, but its short half-life in mice impedes achieving human-like drug exposure profiles. This study aimed to create humanized meropenem dosage regimens in immunocompetent mice with bloodstream infections by Acinetobacter baumannii.

Methods: Cilastatin was administered to prolong the meropenem half-life in mice and match the concentration-time profiles of meropenem in patients. An integrated population pharmacokinetic model was developed to characterize the concentration-dependent inhibition of meropenem clearance by cilastatin. Murine dosage regimens were humanized based on a novel matching framework. Firstly, meropenem plasma concentrations in mice should remain within the 5th to 95th percentiles of plasma concentrations for meropenem monotherapy in critically ill patients. Secondly, the free-time-above-MIC versus MIC profiles of meropenem in mice should match those in patients.

Results: The meropenem half-life in mice increased from 22.2 min without cilastatin to 57.7 min at high cilastatin concentrations. Cilastatin inhibited the meropenem clearance half-maximally at 0.230 mg/L. Subcutaneous doses of 53/10 mg/kg meropenem/cilastatin at 0 h and 26/10 mg/kg at 3 h in mice, both repeated every 8 h, resulted in well-matched pharmacokinetic profiles to those of 2 g meropenem infusions over 30 min at the same dosing interval in patients.

Conclusions: Co-administration of cilastatin substantially prolonged the meropenem half-life in mice and enabled humanized meropenem dosage regimens with six doses per day to stay within the 5th and 95th percentiles of plasma concentrations in patients. This novel framework to humanize murine dosage regimens is based on quantitative matching criteria and supports translational research by achieving clinically relevant exposure profiles in mice.