Development and validation of a population pharmacokinetic model for lacosamide in adult patients with epilepsy to inform precision dosing.

Abstract

BACKGROUND: Lacosamide is a third-generation antiseizure medication that reduces seizures by promoting slow inactivation of voltage-gated sodium channels. There are significant interindividual differences in the pharmacokinetics of this drug. The aim of this study was to explore the pharmacokinetic characteristics of lacosamide in adult patients with epilepsy and to develop a robust population pharmacokinetic model. METHODS: Retrospective data from adult epilepsy patients receiving lacosamide treatment and therapeutic drug monitoring were collected. The population pharmacokinetic model was developed via a nonlinear mixed effects modeling approach. Goodness-of-fit plots (GOF), bootstrap analyses and numerical predictive checks were used to evaluate the final model. RESULTS: A total of 294 plasma concentrations from 180 patients were included. A one-compartment model with first-order absorption and elimination was employed. In the final population pharmacokinetic model for lacosamide, concomitant use of carbamazepine (CBZ), sex and creatine clearance (CLCR) were covariates of drug clearance (CL/F), which can be expressed via the following equation: CL/F = 1.86 × 1.48CBZ×0.875SEX×(CLCR/119)0.311. The estimation of CL/F was 1.86 L/h. The GOF, bootstrap analysis and numerical predictive check indicated that the model was robust. The simulation indicated that the dose of lacosamide should be increased by 40–60% to achieve the original exposure when it is coadministered with CBZ. CONCLUSION: A population pharmacokinetic model for lacosamide in adult patients with epilepsy was successfully established, which will improve model-based precision medication.