title: Impact of cytochrome P450 inducers with or without inhibitors on the serum clobazam level in patients with antiepileptic polypharmacy.
abstract: OBJECTIVE
  The aim of this study was to evaluate the effect of cytochrome P450 (CYP) inducers/inhibitors on the pharmacokinetics of clobazam (CLB) in patients receiving antiepileptic polypharmacy.
  
  
  METHODS
  A total of 2,504 samples obtained from 1,280 patients for routine therapeutic drug monitoring were retrospectively reviewed. These samples were grouped according to the antiepileptic drug regimens or age, and then the concentration to dose (CD) ratio (serum level (ng/ml) divided by dose (mg/kg)) of CLB was calculated for comparison.
  
  
  RESULTS
  The mean CD ratio of CLB in adult patients using enzyme inducers (phenytoin (PHT), carbamazepine (CBZ), and phenobarbital (PB) alone or in combination) was 60.8% lower than the ratio in patients without inducers. Among the inducers, patients using PHT had a significantly lower CD ratio than patients using PB or CBZ (p < 0.001). When PHT was combined with CBZ and/or PB, no additive or synergetic interactions was observed. The CD ratio of CLB in pediatric patients using inducers was 44.3% lower than in patients without inducers. The influence of inducers was unchanged regardless of the child's age, and the effect was stronger in adults than in pediatric patients. Other than inducers, valproic acid (VPA) additively reduced the CD ratio, whereas concomitant use of stiripentol significantly elevated the CD ratio in patients receiving VPA. In contrast, CYP3A4 substrates, such as zonisamide and topiramate, had little influence on the CD ratio of CLB.
  
  
  CONCLUSIONS
  We identified an impact of CYP inducers/inhibitors on the CLB concentration. Our findings demonstrated that clinically relevant interactions occur between CLB and concomitant antiepileptic drugs.
authors.affiliation: Department of Clinical Research, National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, 886, Urushiyama, Shizuoka, 420-8688, Japan, yamamoty-3@hosp.go.jp.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Yukitoshi
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Katsumi
authors.initials: K
authors.lastname: Imai
authors.forename: Masaaki
authors.initials: M
authors.lastname: Takahashi
authors.forename: Masahiko
authors.initials: M
authors.lastname: Nakai
authors.forename: Yushi
authors.initials: Y
authors.lastname: Inoue
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kagawa
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D001569:Benzodiazepines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D000078306:Clobazam; D065693:Cytochrome P-450 Enzyme Inducers / Q000008:administration & dosage / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004827:Epilepsy / Q000188:drug therapy; D005260:Female; D006801:Humans; D008297:Male; D019338:Polypharmacy; D012189:Retrospective Studies
chemical_list: D000927:Anticonvulsants; D065693:Cytochrome P-450 Enzyme Inducers; D065607:Cytochrome P-450 Enzyme Inhibitors; D001569:Benzodiazepines; D000078306:Clobazam