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

Sachiyo Hashi, Ikuko Yano, Mai Shibata, Satohiro Masuda, Masako Kinoshita, Riki Matsumoto, Akio Ikeda, Ryosuke Takahashi, Kazuo Matsubara

Research output: Contribution to journalArticle

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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 (蠇90 % seizure reduction) compared to those with 蠇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.

Original languageEnglish
Pages (from-to)51-58
Number of pages8
JournalEuropean Journal of Clinical Pharmacology
Volume71
Issue number1
DOIs
Publication statusPublished - Jan 1 2015

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Epilepsy
Seizures
Serum
Therapeutics
Cytochrome P-450 CYP2C19
clobazam
Cytochrome P-450 CYP3A
N-desmethylclobazam

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

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Effect of CYP2C19 polymorphisms on the clinical outcome of low-dose clobazam therapy in Japanese patients with epilepsy. / Hashi, Sachiyo; Yano, Ikuko; Shibata, Mai; Masuda, Satohiro; Kinoshita, Masako; Matsumoto, Riki; Ikeda, Akio; Takahashi, Ryosuke; Matsubara, Kazuo.

In: European Journal of Clinical Pharmacology, Vol. 71, No. 1, 01.01.2015, p. 51-58.

Research output: Contribution to journalArticle

Hashi, Sachiyo ; Yano, Ikuko ; Shibata, Mai ; Masuda, Satohiro ; Kinoshita, Masako ; Matsumoto, Riki ; Ikeda, Akio ; Takahashi, Ryosuke ; Matsubara, Kazuo. / Effect of CYP2C19 polymorphisms on the clinical outcome of low-dose clobazam therapy in Japanese patients with epilepsy. In: European Journal of Clinical Pharmacology. 2015 ; Vol. 71, No. 1. pp. 51-58.
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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 (蠇90 {\%} seizure reduction) compared to those with 蠇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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T1 - Effect of CYP2C19 polymorphisms on the clinical outcome of low-dose clobazam therapy in Japanese patients with epilepsy

AU - Hashi, Sachiyo

AU - Yano, Ikuko

AU - Shibata, Mai

AU - Masuda, Satohiro

AU - Kinoshita, Masako

AU - Matsumoto, Riki

AU - Ikeda, Akio

AU - Takahashi, Ryosuke

AU - Matsubara, Kazuo

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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 (蠇90 % seizure reduction) compared to those with 蠇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.

AB - 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 (蠇90 % seizure reduction) compared to those with 蠇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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