Pharmacokinetics of Linezolid Dose Adjustment for Creatinine Clearance in Critically Ill Patients: A Multicenter, Prospective, Open-Label, Observational Study

Abstract

Xipei Wang,1,* Yifan Wang,2,3,* Fen Yao,2,3,* Shenglong Chen,2,* Yating Hou,4 Zhijie Zheng,1 Jinbiao Luo,5 Binghui Qiu,6 Zhanfu Li,7 Yirong Wang,2 Zheng Wu,2 Jinhua Lan,2 Chunbo Chen8,9 1Department of Medical Sciences, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangdong Cardiovascular Institute, Guangzhou, 510080, People’s Republic of China; 2Department of Critical Care Medicine, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, Guangdong, People’s Republic of China; 3School of Biology and Biological Engineering, South China University of Technology, Guangzhou, Guangdong, 510080, People’s Republic of China; 4Department of Oncology, Maoming People’s Hospital, Maoming, 525000, Guangdong, People’s Republic of China; 5Department of Neurosurgery, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510180, People’s Republic of China; 6Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People’s Republic of China; 7Department of Intensive Care Unit, Guangdong 999 Brain Hospital, Guangzhou, 510510, Guangdong, People’s Republic of China; 8Department of Intensive Care Unit of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Laboratory of South China Structural Heart Disease, Guangzhou, 510080, Guangdong, People’s Republic of China; 9The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510000, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chunbo ChenDepartment of Intensive Care Unit of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Laboratory of South China Structural Heart Disease, 96 Dongchuan Road, Guangzhou, 510080, Guangdong, People’s Republic of ChinaEmail [email protected]: The aim of this study is to use a population pharmacokinetic (PK) approach to evaluate the optimal dosing strategy for linezolid (LNZ) in critically ill patients.Methods: This multicenter, prospective, open-label, observational study was conducted in 152 patients, and 117 of them were included in the PK model, whereas the rest were in the validation group. The percentage of therapeutic target attainment (PTTA) comprising two pharmacodynamic indices and one toxicity index was used to evaluate dosing regimens based on Monte Carlo simulations stratified by low, normal, and high renal clearance for MICs of 0.25– 4 mg/L.Results: A single-compartment model with a covariate creatinine clearance (CrCL) was chosen as the final model. The PK parameter estimates were clearance of 5.60 L/h, with CrCL adjustment factor of 0.386, and a distribution volume of 43.4 L. For MIC ≤ 2 mg/L, the standard dosing regimen (600 mg q12h) for patients with severe renal impairment (CrCL, 40 mL/min) and standard dosing or 900 mg q12h for patients with normal renal functions (CrCL, 80 mL/min) could achieve PTTA ≥ 74%. The dose of 2400 mg per 24-h continuous infusion was ideal for augmented renal clearance (ARC) with MIC ≤ 1 mg/L. For MICs > 2 mg/L, rare optimal dose regimens were found regardless of renal function.Conclusion: In critically ill patients, the standard dose of 600 mg q12h was sufficient for MIC ≤ 2 mg/L in patients without ARC. Moreover, a 2400 mg/day 24-h continuous infusion was recommended for ARC patients.Keywords: critically ill patients, linezolid, population pharmacokinetic

Keywords

• critically ill patients
• linezolid
• population pharmacokinetic