title: Pharmacokinetics of clobazam and N-desmethylclobazam in children with dravet syndrome receiving concomitant stiripentol and valproic Acid.
abstract: OBJECTIVE
  The aim of this study was to describe the pharmacokinetics of clobazam and its active metabolite N-desmethylclobazam (N-CLB) in children with Dravet syndrome receiving the stiripentol/valproic acid/clobazam combination therapy of reference and to determine the concentrations of clobazam and N-CLB obtained in this population for the usual 0.2 mg/kg twice-daily dose.
  
  
  METHODS
  Thirty-five children with epilepsy were included in a prospective population pharmacokinetic study (using NONMEM(®) software). Four blood samples were drawn per patient. Area under the plasma concentration-time curve (AUC) and trough concentration (C trough) values for clobazam and N-CLB were simulated for 12,000 theoretical children weighing between 10 and 60 kg.
  
  
  RESULTS
  The pharmacokinetics of clobazam were described by a one-compartment model with first-order absorption, and elimination, formation and elimination of N-CLB were also first-order processes. The apparent total clearance (CL/F) and distribution volume (V CLB/F) of clobazam and the elimination rate constant of N-CLB (Kem) were related to body weight by allometric equations. Mean population estimates (% inter-individual variability) were 1.23 L/h (29%) for CL/F, 39.1 L (18%) for V CLB/F and 0.0706 h(-1) (26%) for Kem. The AUC values for clobazam and N-CLB were found to increase by 100% when bodyweight increased from 10 to 60 kg, and the simulated C trough values were higher than the currently accepted target values (0.03-0.3 mg/L for clobazam and 0.3-3 mg/L for N-CLB).
  
  
  CONCLUSIONS
  This is the first simultaneous pharmacokinetic model for clobazam and N-CLB in epileptic children. Indicative values for the routine therapeutic drug monitoring of clobazam in children with Dravet syndrome treated by stiripentol are provided. The possible consequences of the weight-related changes on clobazam and N-CLB exposures should be further evaluated.
authors.affiliation: Inserm U1129, Paris, France, vincent.jullien@egp.aphp.fr.
authors.forename: Vincent
authors.initials: V
authors.lastname: Jullien
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Chhun
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Rey
authors.forename: Olivier
authors.initials: O
authors.lastname: Dulac
authors.forename: Michel
authors.initials: M
authors.lastname: Tod
authors.forename: Catherine
authors.initials: C
authors.lastname: Chiron
authors.forename: Gérard
authors.initials: G
authors.lastname: Pons
mesh_terms: D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001569:Benzodiazepines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001835:Body Weight / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D000078306:Clobazam; D004148:Dioxolanes / Q000627:therapeutic use*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004831:Epilepsies, Myoclonic / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic; D014635:Valproic Acid / Q000627:therapeutic use*
chemical_list: D000927:Anticonvulsants; D004148:Dioxolanes; D001569:Benzodiazepines; D000078306:Clobazam; D014635:Valproic Acid; C024581:N-desmethylclobazam; C021092:stiripentol