Impact of CYP2C19 polymorphisms on the efficacy of clobazam therapy

Background: Clobazam-induced adverse reactions have been reported in cases with CYP2C19 defective allele(s). However, the relevance of the CYP2C19 genotypes to clobazam therapy remains to be clarified. Methods: The association between CYP2C19 genotypes and the antiepileptic and adverse effects of clobazam was retrospectively investigated in 110 Japanese subjects, in relation to clobazam and N-desmethylclobazam (N-clobazam) concentrations. Results: There were 41 (37.3%) homozygous extensive metabolizers (EMs), 44 (40.0%) heterozygous EMs, and 25 (22.7%) poor metabolizers (PMs). The response rate was significantly greater in PMs and heterozygous EMs than homozygous EMs with a gene-dose effect (65.2, 47.6 and 33.3%, respectively), and the adjusted odds ratio (95% CI) of PM versus homozygous EMs was 9.88 (2.47-39.56; p = 0.001). However, the genotypes did not affect the development of tolerance or adverse reactions, although the incidence of some adverse symptoms was insignificantly higher in PMs. The N-clobazam concentration (mu g/ml) increased with the number of CYP2C19-defective alleles (0.92 +/- 0.61, 2.14 +/- 1.69 and 7.70 +/- 6.04, respectively; p < 0.001), while the clobazam concentration was 1.5-fold greater in those with at least one variant. Conclusion: CYP2C19 genotype had an impact on the efficacy of clobazam, thus indicating that N-clobazam plays an important role in long-term clobazam therapy.