Yaru Peng,1,2,* Yalan Liu,1,* Zeneng Cheng,1 Qiang Zhang,3 Feifan Xie,1 Sucui Zhu,3,4 Sanwang Li1,5,6 

1Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, People’s Republic of China; 2Office of Clinical Trial Institution, Department of Pharmacy, Peking University Shenzhen Hospital, Shenzhen, Guangdong, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 4Department of Nursing, The Third Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 5Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 6Institute of Clinical Pharmacy, Central South University, Changsha, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Sucui Zhu, Department of Respiratory and Critical Care Medicine, The Third Xiangya Hospital, Central South University, Tongzipo Road 138, Changsha, 410013, People’s Republic of China, Tel +86 0731 8861 8080, Email zhusucui2022@163.com Sanwang Li, Department of Pharmacy, The Second Xiangya Hospital, Central South University, Middle Renmin Road 139, Changsha, 410011, People’s Republic of China, Tel/Fax +86 0731 8529 2099, Email sanwangli@csu.edu.cn

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% fT>MIC or 100% fT> 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% fT>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% fT> 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.

Keywords: continuous renal replacement therapy, meropenem, prolonged infusion, population pharmacokinetics, critically ill