title: Concentrations of stiripentol in children and adults with epilepsy:  the influence of dose, age, and comedication.
abstract: BACKGROUND
  Stiripentol (STP) was approved as an orphan drug in 2007 in Europe as adjunctive therapy with valproic acid (VPA) and clobazam (CLB) for Dravet syndrome. Dravet syndrome is a highly pharmacoresistant form of epilepsy, which starts in early childhood. Data about STP pharmacokinetics and interactions are still limited and in part inconsistent. The aim of our study was to analyze the effect of age, gender, daily STP dose per body weight (milligrams per kilogram), VPA, CLB, and enzyme-inducing antiepileptic drugs on STP concentration-to-dose ratio (CDR), STP clearance, and STP trough concentrations.
  
  
  METHODS
  Retrospectively, 220 STP serum concentrations in 75 patients from 3 German Epilepsy Centers were analyzed. Analysis of variance, regression analysis, and generalized estimating equations were used for statistical analysis.
  
  
  RESULTS
  Our findings confirm the nonlinear STP pharmacokinetics. At steady state, STP CDR increased with daily STP doses. Compared with patients older than 12 years, STP concentrations were decreased by 39.6% in children aged 6-12 years (P < 0.001) and by 57.5% in children younger than 6 years (P < 0.001). Phenobarbital and phenytoin decreased STP concentrations by 63.2%. This effect was highly significant (P < 0.001), despite the small number of patients (n = 7) treated with phenobarbital or phenytoin. VPA had no significant effect on STP serum concentrations, whereas STP serum concentrations were moderately but significantly increased by CLB (24.6%, P = 0.011).
  
  
  CONCLUSIONS
  Therapeutic drug monitoring of STP seems to be useful because of the wide variation of STP CDR, the nonlinear concentration-to-dose relationship, age-dependent pharmacokinetics, and drug-drug interactions.
authors: Pharmacological Laboratory, Society for Epilepsy Research, Bielefeld, Germany. Theodor.May@evkb.de
authors: Theodor W
authors: TW
authors: May
authors: Rainer
authors: R
authors: Boor
authors: Thomas
authors: T
authors: Mayer
authors: Uwe
authors: U
authors: Jürgens
authors: Bernhard
authors: B
authors: Rambeck
authors: Nils
authors: N
authors: Holert
authors: Elisabeth
authors: E
authors: Korn-Merker
authors: Christian
authors: C
authors: Brandt
mesh_terms: D000328:Adult; D000367:Age Factors; D000927:Anticonvulsants / Q000627:therapeutic use; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D004148:Dioxolanes / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016903:Drug Monitoring / Q000379:methods*; D004359:Drug Therapy, Combination / Q000379:methods; D004827:Epilepsy / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D010634:Phenobarbital / Q000627:therapeutic use; D010672:Phenytoin / Q000627:therapeutic use; D012044:Regression Analysis; D012189:Retrospective Studies; D012737:Sex Factors; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D004148:Dioxolanes; D010672:Phenytoin; C021092:stiripentol; D010634:Phenobarbital