Population pharmacokinetic model of linezolid and its metabolite PNU-142300 in elderly patients

Background and objectives Elderly patients are at an increased risk of supratherapeutic linezolid exposure, and elevated trough concentrations of linezolid and its metabolite (PNU-142300) are associated with the development of linezolid-induced thrombocytopenia. Clarifying the population pharmacokinetic (PPK) characteristics of linezolid and PNU-142300 in this population is critical for optimizing therapeutic strategies. This study aimed to develop a PPK model for linezolid and PNU-142300 in elderly patients to guide dose adjustments and mitigate thrombocytopenia risk. Methods Patients aged ≥65 years receiving linezolid therapy were enrolled. Concentrations of linezolid and PNU-142300 were quantified using LC-MS/MS. Covariate analysis was conducted via stepwise forward inclusion and backward elimination. Model evaluation included goodness-of-fit plots, prediction-corrected visual predictive checks, and nonparametric bootstrap validation. Monte Carlo simulations were performed to identify optimal dosing regimens. Results A total of 149 concentrations from 114 patients were analysed. Creatinine clearance (CLCr) significantly influenced the clearance of both linezolid and PNU-142300. Population mean estimates for clearance were 2.02 L/h (linezolid) and 1.57 L/h (PNU-142300), with an equal volume of distribution of 31.17 L. The model demonstrated robust stability and predictive performance. For patients with CLCr of 15–29 mL/min, 200 mg q12h achieved optimal linezolid exposure, with a 78.6% probability of maintaining PNU-142300 below the toxicity threshold. For patients with CLCr of 30–89 mL/min, 200 mg q8h provided therapeutic exposure with >80% probability of avoiding metabolite toxicity. Conclusions This first PPK model of linezolid and PNU-142300 in elderly patients supports individualized dosing to reduce thrombocytopenia risk. Linezolid dose reduction may be necessary in elderly patients.