OBJECTIVES: Levetiracetam is a widely used antiseizure drug in patients with refractory epilepsy due to its specific mechanism of action. This study aimed to develop and validate a population pharmacokinetic model (PopPK) to optimize levetiracetam dosing in patients with refractory epilepsy. METHODS: A total of 256 plasma concentrations of levetiracetam, obtained from 135 patients, were employed for PopPK model development, applying a nonlinear mixed-effects modeling methodology. Evaluation of the final model was performed by visually inspecting the goodness-of-fit plots generated, bootstrap resampling, and visual predictive check (VPC). In addition, 60 plasma concentrations, obtained from other 37 patients, were used for external validation of the developed model. RESULTS: A one-compartment model with first-order elimination best described the pharmacokinetic profiles of levetiracetam. Between-patient variability (BPV) was included on apparent clearance (CL/F), and the residual error (RE) was modeled as proportional. The estimates for CL/F, apparent volume of distribution (Vd/F), and absorption rate constant (ka) of the final model were 3.73 L/h, 35.10 L, and 1.35 h SIGNIFICANCE: A reliable PopPK model was successfully developed and validated, offering a valuable tool for tailoring levetiracetam dosing regimens and enhancing drug effectiveness and safety in adult patients with refractory epilepsy.