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Effects of CYP2C19 and CYP2C9 genotypes on pharmacokinetic variability of valproic acid in Chinese epileptic patients: nonlinear mixed-effect modeling

  • Pharmacogenetics
  • Published:
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Abstract

Purpose

To evaluate the effects of CYP2C19 and CYP2C9 genotypes on the pharmacokinetic variability of valproic acid (VPA) in epileptic patients using a population pharmacokinetic (PPK) approach.

Methods

VPA concentrations were measured in 287 epileptic patients, who were genotyped for CYP2C19*2/*3 and CYP2C9*3. Patients who were on monotherapy with VPA were divided into two groups, a PPK-model group (n = 177) and a PPK-valid group (n = 110). The PPK parameter values for VPA were calculated in the PPK-model group by using the NONMEM software. Ultimately, a biological model and a final model were established. Each model was then used to independently predict the concentrations of the PPK-valid group to validate the two models.

Results

There was a significant effect of the CYP2C19 and CYP2C9 genotypes on the pharmacokinetic (PK) variability (P < 0.01) in the final PPK model of CL/F. The interindividual CL was calculated according to the final model: CL/F = 0.0951 × (1 + e0.0267 × (3 − genotype)) + 0.0071 × age (L/h). The coefficient of variation (CV) (omega CL/F) of the final model was 29.3%, while that of the biological model was 31.7%. Based on the genotype, the individual PK parameters can be calculated more accurately than before.

Conclusion

The CYP2C19 and CYP2C9 genotypes significantly influenced the PK variability of VPA, as quantified by NONMEM software.

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Acknowledgements

The authors thank the pharmacists, neurologists, and pediatricians at Xuanwu Hospital of Capital Medical University (Beijing, China) for their contributions to the study.

Author information

Authors and Affiliations

  1. Department of Pharmacy, Xuanwu Hospital of Capital Medical University, Beijing, 100053, China

    Dechun Jiang, Xiangrong Bai, Qingxia Zhang & Yuqin Wang

  2. School of Pharmaceutical Science, Peking University, Beijing, 100083, China

    Wei Lu

  3. Department of Pharmacology, Education Ministry Key Laboratory for Neurodegenerative Diseases, Xuanwu Hospital of Capital Medical University, Beijing, 100053, China

    Dechun Jiang & Lin Li

  4. Department of Clinical Pharmacology, Vienna Medical University, Vienna, 1090, Austria

    Dechun Jiang & Markus Müller

Authors
  1. Dechun Jiang
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  2. Xiangrong Bai
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  3. Qingxia Zhang
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  4. Wei Lu
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  5. Yuqin Wang
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  6. Lin Li
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  7. Markus Müller
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Corresponding author

Correspondence to Yuqin Wang.

Additional information

This project was supported by the National Natural Science Foundation of China (# 30672504).

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Jiang, D., Bai, X., Zhang, Q. et al. Effects of CYP2C19 and CYP2C9 genotypes on pharmacokinetic variability of valproic acid in Chinese epileptic patients: nonlinear mixed-effect modeling. Eur J Clin Pharmacol 65, 1187–1193 (2009). https://doi.org/10.1007/s00228-009-0712-x

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  • DOI: https://doi.org/10.1007/s00228-009-0712-x

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