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

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.

Journal

• European journal of clinical pharmacology

  European journal of clinical pharmacology 71 (1), 51-58, 2014-10-18

  Springer

Keywords

• Clobazam
• N-Desmethylclobazam
• CYP2C19 poor metabolizer
• Low-dose therapy
• Therapeutic drug monitoring
• Adolescent
• Adult
• Aged
• Anticonvulsants/blood
• Anticonvulsants/pharmacokinetics
• Anticonvulsants/therapeutic use
• Asian Continental Ancestry Group/genetics
• Benzodiazepines/blood
• Benzodiazepines/pharmacokinetics
• Benzodiazepines/therapeutic use
• Cytochrome P-450 CYP2C19/genetics
• Epilepsy/blood
• Epilepsy/drug therapy
• Epilepsy/genetics
• Female
• Humans
• Male
• Middle Aged
• Polymorphism, Genetic
• Treatment Outcome
• Young Adult

Details

• CRID: 1050845760746300288
• NII Article ID: 120005657893
• NII Book ID: AA11622529
• ISSN: 14321041
• ISSN: 00316970
• HANDLE: 2433/200178
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • CiNii Articles