Population pharmacokinetics and simulations of imipenem in critically ill patients undergoing continuous renal replacement therapy

Abstract

Various dose regimens of imipenem have been prescribed in critically ill patients undergoing continuous renal replacement therapy (CRRT) but there are limited information on its pharmacokinetics (PK) and treatment efficacy. The aim of this study was to describe the population PK of imipenem in patients receiving CRRT, and utilize this model to inform optimal dosing regimens using pharmacokinetics/pharmacodynamics (PK/PD) target as a surrogate marker for treatment efficacy. Population PK modelling was undertaken in 20 patients receiving CRRT to characterize variabilities and identify influential covariates. Monte Carlo simulations were performed to evaluate differences in probability of target attainment (PTA) between empirically used dosing regimens (0.5 g q6h, 1 g q8h, and 1 g q6h), and to explore the impact of CRRT intensity and identified covariates on target attainment. Imipenem concentration data were adequately described using a one-compartment model. Residual diuresis and burn injury were identified modifiers for imipenem endogenous clearance. The simulations showed that the impact of CRRT intensity on target attainment is clinically irrelevant, whereas urine output and burn injury influence PTA for pathogens with an MIC ≥ 4 mg/L. At an MIC ≤ 2 mg/L, satisfactory PTAs (>80%) were achieved for all three investigated dose regimens regardless of urine output, burn injury, and CRRT intensity. Our results indicate that from a safety perspective, 0.5 g q6h imipenem is optimal in these patients for pathogens with an MIC ≤ 2 mg/L, and 1 g q6h is recommended for non-burn patients with anuria against MIC 4–16 mg/L.