Population Pharmacokinetics of Prolonged Infusion for Meropenem: Tailoring Dosing Recommendations for Chinese Critically Ill Patients on Continuous Renal Replacement Therapy with Consideration for Renal Function

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Objective: Extended meropenem infusion is increasingly employed to enhance clinical outcomes in critically ill patients. Nonetheless, investigations into such dosing regimens in renal-impaired patients undergoing continuous renal replacement therapy (CRRT) are scarce. This study aims to perform a population pharmacokinetic (PK) analysis of prolonged meropenem infusion in critically ill CRRT patients to inform optimal dosing regimens. Methods: Ninety-four concentrations from 21 Chinese critically ill CRRT patients receiving 1 g meropenem every 8– 12 hours infused over 2– 3 hours were utilized to construct the population PK model. Monte Carlo simulations were employed to assess the efficacy based on PK/PD targets (100% f T >MIC or 100% f T > 4×MIC ) and the risk of nephrotoxicity (trough concentration ≥ 45 mg/L) for extended meropenem dosing regimens (0.5– 2 g with a 3-hour infusion administered every 6– 12 hours). Results: Meropenem concentration data was adequately described by a one-compartment model with linear elimination, and creatinine clearance (CLCR) significantly influenced meropenem’s endogenous clearance. 0.5 g q6h and 1 g q8h could achieve desirable attainment of 100% f T >MIC target against an MIC≤ 4 mg/L, with negligible risk of toxicity for CRRT patients across a CLCR range of 10– 50 mL/min. 2 g q6h and 2 g q8h is required for targeting 100% f T > 4×MIC for the patients, but the associated risk of toxicity is very high (> 20%). Conclusion: A population PK model was developed for prolonged meropenem infusion in Chinese CRRT patients, and 0.5 g q6h and 1 g q8h may be the optimal regimen for prolonged infusion.