Drug Metab Dispos. 2025 May 2;53(6):100090. doi: 10.1016/j.dmd.2025.100090. Online ahead of print.
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.
PMID:40424646 | DOI:10.1016/j.dmd.2025.100090
