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

  • Shenghui Mei
  • Weixing Feng
  • Leting Zhu
  • Xingang Li
  • Yazhen Yu
  • Weili Yang
  • Baoqin Gao
  • Xiaojuan Wu
  • Fang Fang
  • Zhigang Zhao
Pharmacokinetics and Disposition
  • 1 Downloads

Abstract

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 × eUGT-CYP for TDD included model and 0.70 × (BSA/0.99)0.57 × eUGT-CYP for BSA included model. The precision of all parameters were acceptable (relative standard error < 32.81%). Bootstrap and visual predictive check results indicated that both two final popPK models were stable with acceptable predictive ability.

Conclusion

TDD, BSA, and genotype might affect VPA clearance in children. The popPK models may be useful for dosing adjustment in children on VPA therapy.

Keywords

Valproic acid Uridine diphosphate glucuronosyltransferase Cytochrome P450 family 2 subfamily C member 19 Clearance Children Population pharmacokinetic model Nonlinear mixed-effects modeling 

Notes

Acknowledgements

Thanks are given to our patients.

Compliance with ethical standards

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

228_2018_2440_MOESM1_ESM.docx (352 kb)
ESM 1 (DOCX 351 kb)
228_2018_2440_MOESM2_ESM.xlsx (299 kb)
ESM 2 (XLSX 298 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pharmacy, Beijing Tiantan HospitalCapital Medical UniversityBeijingPeople’s Republic of China
  2. 2.Department of Clinical Pharmacology, College of Pharmaceutical SciencesCapital Medical UniversityBeijingPeople’s Republic of China
  3. 3.Department of Neurology, Beijing Children’s HospitalCapital Medical UniversityBeijingPeople’s Republic of China
  4. 4.Department of Pediatrics, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina

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