Population pharmacokinetics of meropenem in critically ill adult patients receiving extracorporeal membrane oxygenation-an ASAP ECMO study.

OBJECTIVES

To describe meropenem population pharmacokinetics in critically ill adults receiving extracorporeal membrane oxygenation (ECMO) with or without renal replacement therapy (RRT), and to identify dosing regimens likely to achieve safe and effective exposures.

METHODS

Serial blood samples were collected over a single dosing interval during ECMO. Total plasma concentrations were measured by a validated assay. Population pharmacokinetic modelling and Monte Carlo dosing simulations were performed using Monolix. Dosing regimens were assessed against efficacy targets (Cmin ≥2 or ≥8 mg/L) and a toxicity threshold (Cmin >45 mg/L).

RESULTS

A total of 150 plasma concentration-time points were obtained from 18 patients. Meropenem pharmacokinetics were best described by a two-compartment model with first-order elimination. ECMO flow rate significantly influenced the volume of distribution of the central compartment, while estimated creatinine clearance and concomitant RRT significantly influenced drug clearance. Using the primary efficacy target of 2 mg/L, a meropenem dose of 1 g every 8 h as continuous infusion was the most appropriate regimen for patients with a creatinine clearance of 60-130 mL/min receiving ECMO at a flow rate of 4-6 L/min. In patients receiving RRT, this regimen demonstrated less than 4% probability of reaching toxic concentrations and 100% probability of achieving the efficacy target across all simulated scenarios. The regimen remained robust against the higher efficacy target of 8 mg/L in most scenarios.

CONCLUSIONS

A meropenem dose of 1 g every 8 h as continuous infusion is safe and efficacious in most critically ill patients receiving ECMO with or without concomitant RRT.