Dosing strategies of imipenem in neonates based on pharmacometric modelling and simulation

Abstract

Abstract Objectives Imipenem is a broad-spectrum antibacterial agent used in critically ill neonates after failure of first-line treatments. Few studies have described imipenem disposition in this population. The objectives of our study were: (i) to characterize imipenem population pharmacokinetics (PK) in a cohort of neonates; and (ii) to conduct model-based simulations to evaluate the performance of six different dosing regimens aiming at optimizing PK target attainment. Methods A total of 173 plasma samples from 82 neonates were collected over 15 years at the Lausanne University Hospital, Switzerland. The majority of study subjects were preterm neonates with a median gestational age (GA) of 27 weeks (range: 24–41), a postnatal age (PNA) of 21 days (2–153) and a body weight (BW) of 1.16 kg (0.5–4.1). PK data were analysed using non-linear mixed-effect modelling (NONMEM). Results A one-compartment model best characterized imipenem disposition. Population PK parameters estimates of CL and volume of distribution were 0.21 L/h and 0.73 L, with an interpatient variability (CV%) of 20.1% on CL in a representative neonate (GA 27 weeks, PNA 21 days, BW 1.16 kg, serum creatinine, SCr 46.6 μmol/L). GA and PNA exhibited the greatest impact on PK parameters, followed by SCr. These covariates explained 36% and 15% of interindividual variability in CL, respectively. Simulated regimens using a dose of 20–25 mg/kg every 6–12 h according to postnatal age led to the highest PTA (T>MIC over 100% of time). Conclusions Dosing adjustment according to BW, GA and PNA optimizes imipenem exposure in neonates.