ABCC2 as a novel covariate influencing oxcarbazepine pharmacokinetics in pediatric epilepsy: Insights from population modeling.

Abstract

This study set out to establish a population pharmacokinetic (PPK) model of oxcarbazepine (OXC) in pediatric patients with epilepsy, with the goal of optimizing individualized dosage strategies. We collected steady-state trough plasma concentration data of the OXC active metabolite 10-hydroxycarbazepine from epileptic children. The effects of physiological factors, concomitant medications, and genetic factors on pharmacokinetic parameters were quantitatively examined. Subsequently, a Monte Carlo simulation was carried out to predict steady-state trough concentration under various dosing regimens. A total of 320 plasma samples were obtained from 91 epileptic children. The results of covariate analysis revealed that body weight and ABCC2 rs2273697 had a significant impact on the clearance of the 10-hydroxycarbazepine. The final model demonstrated stable and accurate predictive performance, with simulation results indicating that a dosing regimen of 20-30 mg/kg per day is generally suitable for most pediatric patients to reach therapeutic targets. For children under 2 years, doses over 40 mg/kg per day might be needed. However, for those over 12 kg (2 years), 40-60 mg/kg per day could lead to excessive drug exposure. Patients carrying the ABCC2 variant allele necessitate a lower maintenance dose in comparison to those with the wild-type allele. This study marks the first instance to incorporate the genetic polymorphism of ABCC2 into a PPK model of OXC. The developed PPK model provides a fundamental basis for personalized dosing recommendations of OXC in epileptic children. SIGNIFICANCE STATEMENT: The relationship between 10-hydroxycarbazepine exposure and body weight, as well as the ABCC2 rs2273697 in epileptic children, can be accurately investigated using an age-stratified population pharmacokinetic model. Wild-type ABCC2 rs2273697 exhibited a 25% and 14% higher 10-hydroxycarbazepine apparent clearance compared to homozygous and heterozygous variation patients, respectively. Based on our model, an optimized dosing regimen for oxcarbazepine has been proposed aiming for various subgroups of patients.