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

• Published in: Drug design, development and therapy development and therapy, 2021-01, Vol.15, p.2129-2141
• Main Authors: Wang, Xipei, Wang, Yifan, Yao, Fen, Chen, Shenglong, Hou, Yating, Zheng, Zhijie, Luo, Jinbiao, Qiu, Binghui, Li, Zhanfu, Wang, Yirong, Wu, Zheng, Lan, Jinhua, Chen, Chunbo
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - pharmacokinetics; Antibiotics; Asians; Creatinine; Creatinine - metabolism; Critical Illness; critically ill patients; Dosage; Dosage and administration; Dose-Response Relationship, Drug; Ethylenediaminetetraacetic acid; FDA approval; Female; Glomerular Filtration Rate; Health aspects; Humans; Injections, Intravenous; Kaplan-Meier Estimate; Kidney Function Tests; Linezolid; Linezolid - administration & dosage; Linezolid - pharmacokinetics; Male; Medical research; Medicine, Experimental; Methicillin; Middle Aged; Monte Carlo Method; Observational studies; Original Research; Parameter estimation; Pharmacodynamics; Pharmacokinetics; Pharmacology; Plasma; Population; population pharmacokinetic; Prospective Studies; Proteins; Renal function; Renal Insufficiency - drug therapy; Renal Insufficiency - metabolism; Severity of Illness Index; Staphylococcus infections; Therapeutic targets; Toxicity; Young Adult
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S303497

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. 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. 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. 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.