Model-Based Evaluation of Three-Times-Daily Levetiracetam Dosing in Epilepsy: Population Pharmacokinetic and Simulation Study

Abstract We aimed to explore the adequacy of levetiracetam three times daily dosing in patients with epilepsy by pharmacokinetic modeling and simulation. In this prospective cohort, 27 adult patients diagnosed with epilepsy, who had been on an oral levetiracetam regimen, were included. A population pharmacokinetic model was developed, followed by Monte Carlo simulations to compare the plasma profiles using different doses ranging from 500 to 1500 mg at twice time (BID) and three times daily (TID) frequencies. The final model for levetiracetam concentration was a one-compartment model with linear elimination. The estimated values of the absorption rate (Ka), apparent clearance (CL/F), and apparent volume of distribution (V/F) were 1 hr − 1 , 0.64 L/h, and 2.51 L, respectively. Body weight and concomitant antiseizure medications use significantly influenced CL/F, and body weight also significantly influenced V/F. A clinical trial simulation of 1,000 virtual subjects was generated for each regimen using the final population pharmacokinetic model. The BID regimen produced higher peak and lower trough concentrations, whereas the TID regimen maintained more stable plasma levels throughout the dosing interval. These findings suggest the TID dosing regimen of levetiracetam is expected to provide more sustained plasma concentrations, which may be associated with longer seizure-free periods in patients with epilepsy.