title: Effect of CYP2C19 polymorphisms on the clinical outcome of low-dose clobazam therapy in Japanese patients with epilepsy.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Hashi
authors.forename: Ikuko
authors.initials: I
authors.lastname: Yano
authors.forename: Mai
authors.initials: M
authors.lastname: Shibata
authors.forename: Satohiro
authors.initials: S
authors.lastname: Masuda
authors.forename: Masako
authors.initials: M
authors.lastname: Kinoshita
authors.forename: Riki
authors.initials: R
authors.lastname: Matsumoto
authors.forename: Akio
authors.initials: A
authors.lastname: Ikeda
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Matsubara
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D044466:Asian People / Q000235:genetics*; D001569:Benzodiazepines / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D000078306:Clobazam; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D004827:Epilepsy / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D001569:Benzodiazepines; D000078306:Clobazam; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19