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Pharmacogenetics-based population pharmacokinetic analysis and dose optimization of valproic acid in Chinese southern children with epilepsy: Effect of ABCB1 gene polymorphism

Affiliation
Shenzhen Baoan Women’s and Children’s Hospital ,Jinan University ,Shenzhen ,China
Shen, Xianhuan;
Affiliation
School of Pharmaceutical Sciences ,Health Science Center ,Shenzhen University ,Shenzhen ,China
Chen, Xinyi;
Affiliation
Shenzhen Baoan Women’s and Children’s Hospital ,Jinan University ,Shenzhen ,China
Lu, Jieluan;
Affiliation
Shenzhen Baoan Women’s and Children’s Hospital ,Jinan University ,Shenzhen ,China
Chen, Qing;
Affiliation
Shenzhen Baoan Women’s and Children’s Hospital ,Jinan University ,Shenzhen ,China
Li, Wenzhou;
Affiliation
Shenzhen Baoan Women’s and Children’s Hospital ,Jinan University ,Shenzhen ,China
Zhu, Jiahao;
Affiliation
Shenzhen Baoan Women’s and Children’s Hospital ,Jinan University ,Shenzhen ,China
He, Yaodong;
Affiliation
Shenzhen Baoan Women’s and Children’s Hospital ,Jinan University ,Shenzhen ,China
Guo, Huijuan;
Affiliation
School of Pharmaceutical Sciences ,Health Science Center ,Shenzhen University ,Shenzhen ,China
Xu, Chenshu;
Affiliation
Shenzhen Baoan Women’s and Children’s Hospital ,Jinan University ,Shenzhen ,China
Fan, Xiaomei

Objective: The aim of this study was to establish a population pharmacokinetic (PPK) model of valproic acid (VPA) in pediatric patients with epilepsy in southern China, and provide guidance for individualized medication of VPA therapy. Methods: A total of 376 VPA steady-state trough concentrations were collected from 103 epileptic pediatric patients. The PPK parameter values for VPA were calculated by using the nonlinear mixed-effects modeling (NONMEM) method, and a one-compartment model with first-order absorption and elimination processes was applied. Covariates included demographic information, concomitant medications and selected gene polymorphisms. Goodness-of-fit (GOF), bootstrap analysis, and visual predictive check (VPC) were used for model evaluation. In addition, we used Monte Carlo simulations to propose dose recommendations for different subgroup patients. Results: A significant effect of the patient age and ABCB1 genotypes was observed on the VPA oral clearance (CL/F) in the final PPK model. Compared with patients with the ABCB1 rs3789243 AA genotype, CL/F in patients with GG and AG genotypes was increased by 8% and reduced by 4.7%, respectively. The GOF plots indicated the satisfactory predictive performance of the final model, and the evaluation by bootstrap and VPC showed that a stable model had been developed. A table of individualized dosing regimens involving age and ABCB1 genotype was constructed based on the final PPK model. Conclusion: This study quantitatively investigated the effects of patient age and ABCB1 rs3789243 variants on the pharmacokinetic variability of VPA. The PPK models could be beneficial to individual dose optimization in epileptic children on VPA therapy.

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License Holder: Copyright © 2022 Shen, Chen, Lu, Chen, Li, Zhu, He, Guo, Xu and Fan.

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