Population pharmacokinetics modeling of oxcarbazepine to characterize drug interactions in Chinese children with epilepsy

• Published in: Acta pharmacologica Sinica Vol. 35; no. 10; pp. 1342 - 1350
• Main Authors: Wang, Yang, Zhang, Hua-nian, Niu, Chang-he, Gao, Ping, Chen, Yu-jun, Peng, Jing, Liu, Mao-chang, Xu, Hua
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2014; Nature Publishing Group
• Subjects: Adolescent; Anticonvulsants - pharmacokinetics; Anticonvulsants - therapeutic use; Biomedical and Life Sciences; Biomedicine; Carbamazepine - analogs & derivatives; Carbamazepine - pharmacokinetics; Carbamazepine - therapeutic use; Child; Child, Preschool; Drug Interactions; Epilepsy - drug therapy; Female; Humans; Immunology; Infant; Internal Medicine; Male; Medical Microbiology; Models, Biological; Original; original-article; Oxcarbazepine; Pharmacology/Toxicology; Vaccine; 中国; 儿童; 动学模型; 抗癫痫药; 活性代谢产物; 群体; 药物相互作用; 预测误差; epilepsy; oxcarbazepine; CYP450; 10-hydroxycarbazepine; drug interaction; Chinese children; population pharmacokinetics; pediatric patients
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/aps.2014.76

Aim： To develop a population pharmacokinetics model of oxcarbazepine in Chinese pediatric patients with epilepsy, and to study the interactions between oxcarbazepine and other antiepileptic drugs （AEDs）. Methods： A total of 688 patients with epilepsy aged 2 months to 18 years were divided into model （n=573） and valid （n=115） groups. Serum concentrations of the main active metabolite of oxcarbazepine, lO-hydroxycarbazepine （MHD）, were determined 0.5-48 h after the last dosage. A population pharmacokinetics （PPK） model was constructed using NLME software. This model was internally evaluated using Bootstrapping and goodness-of-fit plots inspection. The data of the valid group were used to calculate the mean prediction error （MPE）, mean absolute prediction error （MAE）, mean squared prediction error （MSE） and the 95% confidence intervals （95% CI） to externally evaluate the model. Results： The population values of pharmacokinetic parameters estimated in the final model were as follows： Ka=0.83 h-1, Vd=0.67 L/kg, and CL=0.035 L·kg-1·h-1. The enzyme-inducing AEDs （carbamazepine, phenytoin, phenobarbital） and newer generation AEDs （levetiracetam, lamotrigine, topiramate） increased the weight-normalized CL value of MHD by 17.4% and 10.5%, respectively, whereas the enzyme-inhibiting AED valproic acid decreased it by 3%. No significant association was found between the CL value of MHD and the other covariates. For the final model, the evaluation results （95% CI） were MPE=0.01 （-0.07-0.10） mg/L, MAE=0.46 （0.40-0.51） mg/L, MSE=0.39 （0.27-0.51） （mg/L）2. Conclusion： A PPK model of OXC in Chinese pediatric patients with epilepsy is established. The enzyme-inducing AEDs and some newer generation AEDs （lamotrigine, topiramate） could slightly increase the metabolism of MHD.