Population Pharmacokinetic Meta-Analysis and Dosing Recommendation for Meropenem in Critically Ill Patients Receiving Continuous Renal Replacement Therapy

The optimal dosing regimen for meropenem in critically ill patients undergoing continuous renal replacement therapy (CRRT) remains undefined due to small studied sample sizes and uninformative pharmacokinetic (PK)/pharmacodynamic (PD) analyses in reported studies. The present study aimed to perform a population PK/PD meta-analysis of meropenem using available literature data to suggest the optimal treatment regimen. A total of 501 meropenem concentration measurements from 78 adult CRRT patients pooled from nine published studies were used to develop the population PK model for meropenem. PK/PD target (40% and 100% of the time with the unbound drug plasma concentration above the MIC) marker-based efficacy and risk of toxicity (trough concentrations of >45 mg/L) for short-term (30 min), prolonged (3 h), and continuous (24 h) infusion dosing strategies for meropenem were investigated. The impact of CRRT dose and identified covariates on the PD probability of target attainment (PTA) and predicted toxicity was also examined. Meropenem concentration data were adequately described by a two-compartment model with linear elimination. Trauma was identified as a pronounced modifier for endogenous clearance of meropenem. Simulations demonstrated that adequate PK/PD targets and low risk of toxicity could be achieved in non-trauma CRRT patients receiving meropenem regimens of 1 g every 6 h infused over 30 min, 1 g every 8 h infused over 3 h, and 2 to 4 g every 24 h infused over 24 h. The impact of CRRT dose (25 to 50 mL/kg/h) on PTA was clinically irrelevant, and continuous infusion of 3 to 4 g every 24 h was suitable for trauma CRRT patients (MICs of ≤0.5 mg/L). A population PK model was developed for meropenem in CRRT patients, and different dosing regimens were proposed for non-trauma and trauma CRRT patients.