title: Effectiveness of add-on stiripentol to clobazam and valproate in Japanese patients with Dravet syndrome: additional supportive evidence.
abstract: OBJECTIVE
  To evaluate the efficacy and safety of stiripentol as add-on therapy in Japanese patients with Dravet syndrome treated with clobazam (CLB) and valproate (VPA).
  
  
  METHODS
  In this open-label study, patients aged 1-30 years entered a 4-week baseline phase, followed by a 4-week stiripentol dose-adjustment and 12-week fixed-dose phase. The primary efficacy endpoint was responder rate (proportion of patients with a ≥50% reduction from baseline phase in clonic or tonic-clonic seizure frequency over the last 4 weeks of fixed-dose treatment [target phase]). Safety and pharmacokinetics were also assessed.
  
  
  RESULTS
  Of 27 patients screened in the baseline phase, 24 patients entered the dose-adjustment phase. All patients completed the study. Responder rate was 66.7% (16/24, 95% CI: 44.7-84.4%), and four patients became free from clonic or tonic-clonic seizures. The duration of clonic or tonic-clonic seizures was also significantly reduced in the target versus baseline phase. The most frequent adverse events were somnolence, anorexia, ataxia, nasopharyngitis and γ-glutamyl transpeptidase increase, all of which were of mild-to-moderate severity. Stiripentol plasma concentration in the fixed-dose phase was 4-25 μg/mL. After adding stiripentol to CLB and VPA, the minimum plasma concentrations of CLB and N-desmethyl-CLB (NCLB) increased and that of 4'-hydroxy-N-desmethyl-CLB(OH-NCLB) decreased, while those of VPA and bromide (optionally used) were not affected.
  
  
  CONCLUSIONS
  Add-on stiripentol to CLB and VPA was well tolerated and significantly decreased clonic or tonic-clonic seizures in patients with Dravet syndrome.
authors.affiliation: National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Urushiyama 886, Aoi-ku, Shizuoka 420-8688, Japan. Electronic address: yinoue-jes@umin.net.
authors.forename: Yushi
authors.initials: Y
authors.lastname: Inoue
authors.affiliation: Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ohtsuka
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D044466:Asian People; D001569:Benzodiazepines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D000078306:Clobazam; D004148:Dioxolanes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004831:Epilepsies, Myoclonic / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007223:Infant; D007564:Japan; D008297:Male; D016896:Treatment Outcome; D014635:Valproic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D004148:Dioxolanes; D001569:Benzodiazepines; D000078306:Clobazam; D014635:Valproic Acid; C021092:stiripentol
keywords: Dravet syndrome; Efficacy; Pharmacokinetics; Stiripentol; Tolerability