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A Population Pharmacokinetic Model of Valproic Acid in Pediatric Patients with Epilepsy: A Non-Linear Pharmacokinetic Model Based on Protein-Binding Saturation

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Abstract

Background and Objective

Valproic acid (VPA) follows a non-linear pharmacokinetic profile in terms of protein-binding saturation. The total daily dose regarding VPA clearance is a simple power function, which may partially explain the non-linearity of the pharmacokinetic profile; however, it may be confounded by the therapeutic drug monitoring effect. The aim of this study was to develop a population pharmacokinetic model for VPA based on protein-binding saturation in pediatric patients with epilepsy.

Methods

A total of 1,107 VPA serum trough concentrations at steady state were collected from 902 epileptic pediatric patients aged from 3 weeks to 14 years at three hospitals. The population pharmacokinetic model was developed using NONMEM® software. The ability of three candidate models (the simple power exponent model, the dose-dependent maximum effect [DDE] model, and the protein-binding model) to describe the non-linear pharmacokinetic profile of VPA was investigated, and potential covariates were screened using a stepwise approach. Bootstrap, normalized prediction distribution errors and external evaluations from two independent studies were performed to determine the stability and predictive performance of the candidate models.

Results

The age-dependent exponent model described the effects of body weight and age on the clearance well. Co-medication with carbamazepine was identified as a significant covariate. The DDE model best fitted the aim of this study, although there were no obvious differences in the predictive performances. The condition number was less than 500, and the precision of the parameter estimates was less than 30 %, indicating stability and validity of the final model.

Conclusion

The DDE model successfully described the non-linear pharmacokinetics of VPA. Furthermore, the proposed population pharmacokinetic model of VPA can be used to design rational dosage regimens to achieve desirable serum concentrations.

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Acknowledgments

This work was partially presented at the 2013 International Symposium of Quantitative Pharmacology, Beijing, China. The authors would like to thank Professor Nick Holford of the University of Auckland, New Zealand for his invaluable advice.

This project was partly supported by the National Natural Science Foundation of China (No. 81072702) and the Major Research and Development Project of Innovative Drugs, China Ministry of Science and Technology (2012ZX09303004-001).

Conflicts of interest

All authors declare no conflicts of interest.

Author information

Authors and Affiliations

  1. Children’s Hospital, Fudan University, Shanghai, China

    Junjie Ding & Yi Wang

  2. Department of Pharmacy, The First Hospital Affiliated to Fujian Medical University, Fuzhou, China

    Weiwei Lin & Changlian Wang

  3. Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, China

    Limei Zhao

  4. Department of Pharmacy, Beijing Tian Tan Hospital, Capital Medical University, Beijing, China

    Xingang Li & Zhigang Zhao

  5. Department of Pharmacy, The First Hospital affiliated to Soochow University, Soochow, China

    Liyan Miao

  6. Department of Pharmacy, Huashan Hospital, Fudan University, 12 Wu Lu Mu Qi M Rd, Shanghai, 200040, China

    Zheng Jiao

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  1. Junjie Ding
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  3. Weiwei Lin
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Corresponding author

Correspondence to Zheng Jiao.

Additional information

J. Ding and Y. Wang contributed equally to this study.

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Ding, J., Wang, Y., Lin, W. et al. A Population Pharmacokinetic Model of Valproic Acid in Pediatric Patients with Epilepsy: A Non-Linear Pharmacokinetic Model Based on Protein-Binding Saturation. Clin Pharmacokinet 54, 305–317 (2015). https://doi.org/10.1007/s40262-014-0212-8

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