Original Article

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

Authors: Yang Wang, Hua-nian Zhang, Chang-he Niu, Ping Gao, Yu-jun Chen, Jing Peng, Mao-chang Liu, Hua Xu
DOI: 10.1038/aps.2014.76

Abstract

Yang WANG, Hua-nian ZHANG1, *, Chang-he NIU, Ping GAO, Yu-jun CHEN, Jing PENG, Mao-chang LIU, Hua XU
Department of Pharmacy, Wuhan Children’s Hospital, 100th-Hong Kong Road, Wuhan 430016, China

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, 10-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.


Keywords: epilepsy; oxcarbazepine; 10-hydroxycarbazepine; population pharmacokinetics; drug interaction; CYP450; pediatric patients; Chinese children

This project was supported by the Scientific Research Foundation of Clinical Medicine of Wuhan City (No WX14C47).
* To whom correspondence should be addressed.
E-mail cattop3211@sohu.com
Received 2014-03-04 Accepted 2014-07-04
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