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Effect of CYP2C19 polymorphisms on the clinical outcome of low-dose clobazam therapy in Japanese patients with epilepsy

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Clobazam (CLB) is metabolized by cytochrome P450 (CYP) 3A4 to yield N-desmethylclobazam (N-CLB), which is further inactivated by CYP2C19. The aim of this study was to retrospectively evaluate the relationship between CYP2C19 polymorphisms and the efficacy of low-dose, add-on CLB therapy in Japanese patients with epilepsy.

Methods

Fifty patients were divided into three groups according to their CYP2C19 polymorphism. CLB and N-CLB serum concentrations and seizure frequency before and after starting CLB were analyzed.

Results

Extensive metabolizers (EMs, n = 11), intermediate metabolizers (IMs, n = 22), and poor metabolizers (PMs, n = 17) were included. Although the dose-normalized CLB serum concentrations were not significantly different, the dose-normalized N-CLB serum concentrations were significantly higher in PMs than in EMs or IMs. Seizure frequency was significantly decreased by the CLB therapy in PMs (p < 0.01), but not in EMs or IMs. CLB serum concentrations did not correlate with seizure reduction rate, but median N-CLB serum concentrations were significantly higher in patients with excellent seizure control (≧90 % seizure reduction) compared to those with ≧50 % seizure reduction or with <50 % seizure reduction (1103, 341, and 570 ng/mL, respectively).

Conclusions

The efficacy of low-dose CLB therapy was significantly influenced by CYP2C19 polymorphisms. Ideally, CLB therapy should be started with a low dose (2.5 mg/day) and dosage increased until N-CLB serum concentration reaches 1100 ng/mL or until the desired effect is acquired, a recommendation that is particularly important for PMs.

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Acknowledgments

This work was partially supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Conflict of interest

None of the authors has any conflict of interest related to this study.

Author information

Author notes

  1. Riki Matsumoto & Akio Ikeda

    Present address: Department of Epilepsy, Movement Disorders and Physiology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan

  2. Satohiro Masuda

    Present address: Department of Pharmacy, Kyushu University Hospital, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

Authors and Affiliations

  1. Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto, 606-8507, Japan

    Sachiyo Hashi, Ikuko Yano, Mai Shibata, Satohiro Masuda & Kazuo Matsubara

  2. Department of Clinical Pharmacy and Education, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan

    Ikuko Yano & Mai Shibata

  3. Department of Neurology, Utano National Hospital, National Hospital Organization, Ukyo-ku, Kyoto, 616-8255, Japan

    Masako Kinoshita

  4. Department of Neurology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan

    Riki Matsumoto, Akio Ikeda & Ryosuke Takahashi

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  1. Sachiyo Hashi
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Correspondence to Ikuko Yano.

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Hashi, S., Yano, I., Shibata, M. et al. Effect of CYP2C19 polymorphisms on the clinical outcome of low-dose clobazam therapy in Japanese patients with epilepsy. Eur J Clin Pharmacol 71, 51–58 (2015). https://doi.org/10.1007/s00228-014-1773-z

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  • DOI: https://doi.org/10.1007/s00228-014-1773-z

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