Population Pharmacokinetic and Pharmacodynamic Analysis of Imipenem in Critically Ill Patients Receiving Continuous Renal Replacement Therapy

Le résumé fourni par la source

Background: Imipenem pharmacokinetics exhibit substantial variability in critically ill patients receiving continuous renal replacement therapy (CRRT) due to pathophysiological alterations and extracorporeal clearance, challenging empirical dosing strategies. Population pharmacokinetic studies specifically in critically ill patients receiving CRRT remain limited, and pharmacodynamic target attainment across different CRRT modalities has not been adequately characterized. As a hydrophilic β-lactam antibiotic with low protein binding and predominant renal elimination, imipenem is highly susceptible to pharmacokinetic alterations caused by CRRT and critical illness. In addition to increased capillary permeability and edema, factors such as fluid resuscitation, hypoalbuminemia, altered organ perfusion, and unstable renal function may further influence drug distribution and clearance. Objective: This study aims to develop a population pharmacokinetic (PopPK) model for imipenem in critically ill patients receiving CRRT and to evaluate the probability of target attainment (PTA) for achieving a 40% fT>MIC across various clinical scenarios and dosing regimens. Methods: Clinical data were retrospectively collected from 46 critically ill patients receiving CRRT, yielding a total of 560 plasma samples and 280 waste fluid samples. A PopPK model was developed using the nonlinear mixed-effects modelling (NONMEM) method, and statistically significant covariates were incorporated. Subsequently, Monte Carlo simulations (1000 virtual patients per dosing scenario) were performed to evaluate the pharmacodynamic target attainment of different dosing regimens across various levels of creatinine clearance (CrCl), pathogen minimum inhibitory concentrations (MIC), and CRRT modalities (CVVH and CVVHDF). Results: The pharmacokinetics of imipenem in critically ill patients receiving CRRT were best described by a two-compartment model. The typical population clearance and central volume of distribution were 6.08 L/h and 24.4 L, respectively. CrCl was identified as a significant covariate affecting imipenem clearance (2.1.1) in which CrCl was identified as a significant covariate affecting clearance. Monte Carlo simulations indicated that imipenem achieved satisfactory PTA across subgroups when MIC ≤ 2 mg/L. However, when MIC increased to 8 mg/L in the context of high clearance, dose escalation to 1 g q6h was required to ensure adequate target attainment. When MIC ≥ 16 mg/L, further dose intensification alone was insufficient to overcome the impact of enhanced drug clearance, and combination therapy should be considered. Conclusion: By developing a PopPK model for imipenem, this study confirmed the significant impact of CrCl on drug clearance in patients undergoing CRRT. These findings provide a theoretical basis for optimizing PK/PD target-oriented individualized dosing regimens in this patient population.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.