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

Abstract

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.

Keywords: NONMEM; continuous renal replacement therapy; critically ill; meropenem; population pharmacokinetics.

FIG 1

GOF plots for the final population PK model of meropenem. (Top left) Observed concentrations versus population predictions for meropenem. (Top right) Observed concentrations versus individual predictions for meropenem. (Bottom left) Conditional weighted residuals (CWRES) versus population predictions of meropenem concentrations. (Bottom right) CWRES versus time after dose. Gray crosses represent meropenem concentrations or CWRES values. The solid black lines depict the correlations of our observations and predictions; the dashed lines are reference lines of unity or CWRES borders.

FIG 2

pc-VPC plot for the final population PK model of meropenem in CRRT patients. The black dots represent the observed meropenem concentrations. The solid and dashed lines represent the 5th, 50th, and 95th percentiles for the observed and simulated data, respectively. The shaded areas represent the 90% prediction intervals.

FIG 3

Boxplots for the post hoc individual CL_total, CL_body, and V₁ values for meropenem across different CRRT studies. (a and b) Model-predicted CL_total for non-trauma patients (a) and trauma patients (b). (c and d) Model-predicted CL_body for non-trauma patients (c) and trauma patients (d). (e) Predicted V₁ values in different studies. In the boxplots, the lower boundary of the box indicates the 25th percentile, the line within the box marks the 50th percentile, and the upper boundary of the box represents the 75th percentile. Whiskers above and below the box indicate 1.5 times the interquartile range below the 25th percentile and above the 75th percentile, respectively. Points above and below the whiskers are defined as outliers.

FIG 4

PTA versus MIC profiles for different meropenem dosing regimens in non-trauma patients receiving a CRRT dose of 35 mL/h/kg based on the PK/PD targets of 40% fT_>MIC (a and c) and 100% fT_>MIC (b and d). The dashed horizontal lines represent a PTA of 90%.