title: A physiologically based pharmacokinetic model for clobazam and stiripentol in adults and children.
abstract: OBJECTIVE
  To develop a physiologically based pharmacokinetic model in adults and children for clobazam, its active metabolite norclobazam and stiripentol and to account for significant clinical interaction that has been reported when clobazam and stiripentol are co-administered.
  
  
  METHODS
  A PBPK model with ten compartments was developed. An in vitro-in vivo extrapolation technique was used to scale clearance in children for clobazam and norclobazam and clearance parameters for stiripentol were obtained from fitting. Other drug and system parameters were obtained from the literature.
  
  
  RESULTS
  The tissue/blood partition coefficients adequately predict observed volume of distribution for clobazam and stiripentol. In a clinical study in children where clobazam was administered alone and co-administered with stiripentol, the predicted and observed minimum concentration at steady state (mean and 95% confidence interval) during clobazam monotherapy were 0.19 (0.05-0.49 mg/L) and 0.20 (0.17-0.23 mg/L), respectively, and predicted and observed norclobazam concentrations were 0.49 (0.16-1.38 mg/L) and 0.95 (0.91-0.99 mg/L), respectively. From an interaction study with stiripentol the predicted stiripentol concentration was 10.12 (2.51-39.36 mg/L) and the observed concentration was 10.0 (8.3-11.7 mg/L); the predicted clobazam concentration was 0.29 (0.07-1.05 mg/L) and the observed concentration was 0.31 (0.24-0.38 mg/L); and the predicted norclobazam concentration was 2.30 (0.45-5.53 mg/L) and the observed concentration was 4.32 (3.77-4.87 mg/L).
  
  
  CONCLUSIONS
  The PBPK model adequately described observed data and the extent of interaction between clobazam/norclobazam and stiripentol.
authors: Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, The University of Manchester, Oxford Road, Manchester, M13 9PT, UK, kayode.ogungbenro@manchester.ac.uk.
authors: Kayode
authors: K
authors: Ogungbenro
authors: Leon
authors: L
authors: Aarons
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001569:Benzodiazepines / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D002648:Child; D000078306:Clobazam; D003198:Computer Simulation; D004148:Dioxolanes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006801:Humans; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D014018:Tissue Distribution
chemical_list: D000927:Anticonvulsants; D004148:Dioxolanes; D001569:Benzodiazepines; D000078306:Clobazam; C024581:N-desmethylclobazam; C021092:stiripentol