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

Eur J Clin Pharmacol. 2015 Jan;71(1):51-8. doi: 10.1007/s00228-014-1773-z. Epub 2014 Oct 18.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Anticonvulsants* / blood
  • Anticonvulsants* / pharmacokinetics
  • Anticonvulsants* / therapeutic use
  • Asians / genetics*
  • Benzodiazepines* / blood
  • Benzodiazepines* / pharmacokinetics
  • Benzodiazepines* / therapeutic use
  • Clobazam
  • Cytochrome P-450 CYP2C19 / genetics*
  • Epilepsy* / blood
  • Epilepsy* / drug therapy
  • Epilepsy* / genetics
  • Female
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Genetic
  • Treatment Outcome
  • Young Adult

Substances

  • Anticonvulsants
  • Benzodiazepines
  • Clobazam
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP2C19