Effect of CYP2C19, UGT1A8, and UGT2B7 on valproic acid clearance in children with epilepsy: a population pharmacokinetic model

• Published in: European journal of clinical pharmacology 2018-08, Vol.74 (8), p.1029-1036
• Main Authors: Mei, Shenghui, Feng, Weixing, Zhu, Leting, Li, Xingang, Yu, Yazhen, Yang, Weili, Gao, Baoqin, Wu, Xiaojuan, Fang, Fang, Zhao, Zhigang
• Format: Article
• Language: English
• Subjects: Biomedical and Life Sciences; Biomedicine; Children; Epilepsy; Genetic diversity; Genetic variance; Genotypes; Metabolism; Pharmacokinetics; Pharmacokinetics and Disposition; Pharmacology/Toxicology; Seizures; Single-nucleotide polymorphism; Standard error; Valproic acid
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-018-2440-6

Purpose Valproic acid (VPA) is an important drug in seizure control with great inter-individual differences in metabolism and treatment effect. This study aims to identify the effects of genetic variants on VPA clearance in a population pharmacokinetic (popPK) model in children with epilepsy. Methods A total of 325 VPA plasma concentrations from 290 children with epilepsy were used to develop the popPK model by using the nonlinear mixed-effects modeling method. The one-compartment model was established to describe the pharmacokinetics of VPA. Twelve single nucleotide polymorphisms involved in the pharmacokinetics of VPA were identified by MassARRAY system and their effects on VPA clearance were evaluated. Results In the two final popPK models, inclusion of a combined genotype of four variants (rs1042597, rs28365062, rs4986893, and rs4244285), total daily dose (TDD), and body surface area (BSA) significantly reduced inter-individual variability for clearance over the base model. The inter-individual clearance equals to 0.73 × (TDD/628.92) 0.59  × e UGT-CYP for TDD included model and 0.70 × (BSA/0.99) 0.57  × e UGT-CYP for BSA included model. The precision of all parameters were acceptable (relative standard error