Population Pharmacokinetics of Linezolid in Elderly Hospitalized Patients: Implications for Therapeutic Drug Monitoring

Background: Linezolid is widely used for the empirical and targeted treatment of Gram-positive infections. Elderly patients frequently exhibit substantial pharmacokinetic variability due to age-related physiological changes and high comorbidity burden, which may predispose to drug accumulation and toxicity. This study aimed to develop and evaluate a population pharmacokinetic (PopPK) model of intravenous (IV) linezolid in elderly patients (65–87 years) to support therapeutic drug monitoring and explore exposure-risk scenarios associated with overexposure. Methods: A retrospective single-center study including 149 patients and 293 serum trough concentrations was conducted. Patients were randomly assigned to development (n = 103) and independent validation (n = 46) cohorts. Linezolid concentrations were quantified using an enzyme immunoassay. The PopPK model was developed in NONMEM® using FOCE-I. Model performance was evaluated using standard diagnostic plots, bootstrap analysis, visual predictive checks, and validation metrics (mean prediction error [MPE] and mean absolute prediction error [MAPE]). Monte Carlo simulations assessed the probability of overexposure (Cmin > 8 mg/L) and the probability of target attainment (PTA; AUC24/MIC ≥ 100) under standard dosing (600 mg IV every 12 h). Results: Linezolid pharmacokinetics were best described by a one-compartment model with first-order elimination. Estimated glomerular filtration rate, treatment duration, and age were identified as significant predictors of clearance. Internal and independent validation confirmed the robustness and predictive performance of the model. Simulations showed a high probability of overexposure in patients with impaired renal function, particularly during prolonged treatment. Conclusions: Renal function, age, and treatment duration are major determinants of linezolid exposure in elderly patients. Standard dosing frequently results in overexposure, supporting early therapeutic drug monitoring and individualized dose adjustment in this vulnerable population.