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Population pharmacokinetics of valproic acid in adult Chinese patients with bipolar disorder

  • Pharmacokinetics and Disposition
  • Published:
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Abstract

Purpose

To develop and validate a population pharmacokinetic (PPK) model of valproic acid (VPA) in adult Chinese patients with bipolar disorder, and provide guidance for individualized therapy in this population.

Methods

A total of 1104 serum concentrations from 272 patients were collected in this study. The data analysis was performed using a nonlinear mixed-effects modeling approach. Covariates included demographic parameters, biological characteristics, and concomitant medications. Bootstrap validation (1000 runs), normalized prediction distribution error (NPDE), and external validation of 50 patients were employed to evaluate the final model.

Results

A one-compartment model with first-order absorption and elimination was developed for VPA extended-release tablets. VPA clearance was significantly influenced by three variables: sex (12% higher in male patients), daily dose (increasing with the 0.13 exponent), and body weight (increasing with the 0.56 exponent). Typical values for the absorption rate constant (Ka), apparent clearance (CL/F), and apparent distribution volume (V/F) for a female patient weighing 70 kg administered VPA 1000 mg/day were 0.18 h−1, 0.46 L/h, and 12.84 L, respectively. The results of model evaluation indicated a good stable and precise performance of the final model.

Conclusions

A qualified PPK model of VPA was developed in Chinese patients with bipolar disorder. This model could be used as a suitable tool for the personalization of VPA dosing for bipolar patients.

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Acknowledgements

The authors are grateful to all the patients who participated in this study, and all the medical staff in Beijing Anding Hospital who helped conduct this study.

Funding

This study was supported by Capital’s Funds for Health Improvement and Research (Grant No. 2018–4-2124), 2019 NARSAD Young Investigator Award from the Brain & Behavior Research Foundation (Grant No. 28141), National Natural Science Foundation of China (Grant No. 81801322), Beijing Municipal Administration of Hospitals Incubating Program (Grant No. PX2019070).

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Authors and Affiliations

  1. The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China

    Yan-Nan Zang, Wei Guo, Meng-Xi Niu, Shuang Bao, Qian Wang, Yan Wang, Fang Dong, An-Ning Li & Can-Jun Ruan

  2. Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China

    Yan-Nan Zang, Wei Guo, Meng-Xi Niu, Shuang Bao, Qian Wang, Yan Wang, Fang Dong, An-Ning Li & Can-Jun Ruan

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  1. Yan-Nan Zang
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Contributions

YNZ, CJR, and WG were involved in the concept and design of the study. MXN, SB, QW, YW, FD, and ANL were involved in patient recruitment. CJR conducted the analyses of VPA serum concentrations. YNZ and CJR conducted the statistical analyses. YNZ wrote the first draft of the article manuscript, and all authors contributed to subsequent drafts and gave final approval of the version to be published.

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Correspondence to Can-Jun Ruan.

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The protocol for the study was approved by the Research Ethics Committee of Beijing Anding Hospital (ethical code: 201965FS-2).

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Written informed consent was obtained from all patients.

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The authors declare that they have no conflict of interest.

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Zang, YN., Guo, W., Niu, MX. et al. Population pharmacokinetics of valproic acid in adult Chinese patients with bipolar disorder. Eur J Clin Pharmacol 78, 405–418 (2022). https://doi.org/10.1007/s00228-021-03246-2

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