Population pharmacokinetics of levetiracetam in patients diagnosed with refractory epilepsy: A real-world study

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.

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.

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^-1, respectively. BPV associated with CL/F was 18.30%, and the proportional RE was 21.21%. The co-administration of other antiseizure drugs that are metabolic inducers, the glomerular filtration rate, and the body weight were identified as significant covariates for CL/F, whereas body surface area was the only covariate with significant impact on the Vd/F. The bootstrap, VPC, and external evaluation collectively validated the stability and predictive performance of the final model.

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.