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