title: Add-on stiripentol elevates serum valproate levels in patients with or without concomitant topiramate therapy.
abstract: Stiripentol (STP), valproate (VPA) and topiramate (TPM) are reported to have efficacy for Dravet syndrome. In this study, we sought to elucidate the mechanisms underlying the increased serum VPA concentrations following STP adjunctive therapy in patients with Dravet syndrome.
  
  
  
  Twenty-eight patients with Dravet syndrome (age range, 1-35 years) undergoing combination therapy with VPA and STP were included in this study. We evaluated VPA and clobazam (CLB) serum concentrations before and after add-on STP. We also investigated potential factors impacting VPA metabolism during add-on STP therapy, including add-on TPM and CYP2C9 and CYP2C19 gene polymorphisms. The effect of STP on the metabolism of concomitantly administered CLB was also investigated.
  
  
  
  Add-on STP was significantly associated with the serum concentration-to-dose (CD) ratio of VPA. Two patients, who were concomitantly treated with TPM, developed severe anorexia and thrombocytopenia because of marked increases in serum VPA concentrations. Further analysis revealed that the rate of increase in the VPA CD ratio was positively correlated with TPM dose. In patients not receiving TPM, STP enhanced the rate of increase in the VPA CD ratio to a significantly greater extent in CYP2C19 extensive metabolizers than in CYP2C19 poor metabolizers. Add-on STP was also associated with significant increases in CLB and N-desmethyl-CLB serum concentrations.
  
  
  
  Our findings suggest that serum VPA concentrations should be carefully monitored during STP adjunctive therapy, particularly in patients receiving concomitant TPM therapy.
authors.affiliation: Department of Pediatrics, Ehime Prefectural Central Hospital, Japan; Department of Pediatrics, Ehime University Graduate School of Medicine, Japan. Electronic address: j_104hiro@yahoo.co.jp.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Jogamoto
authors.affiliation: National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Japan. Electronic address: yamamoty@shizuokamind.org.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Department of Pediatrics, Ehime University Graduate School of Medicine, Japan. Electronic address: fukumits@m.ehime-u.ac.jp.
authors.forename: Mitsumasa
authors.initials: M
authors.lastname: Fukuda
authors.affiliation: Department of Pediatrics, Ehime University Graduate School of Medicine, Japan. Electronic address: yusuzuki777@gmail.com.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Japan. Electronic address: imaik@szec.hosp.go.jp.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Imai
authors.affiliation: National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Japan. Electronic address: takahashi-ped@umin.ac.jp.
authors.forename: Yukitoshi
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Japan. Electronic address: jes@umin.net.
authors.forename: Yushi
authors.initials: Y
authors.lastname: Inoue
authors.affiliation: Department of Child Neurology, Asahigawaso Rehabilitation and Medical Center, Japan. Electronic address: ohtsuka@okayama-u.ac.jp.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ohtsuka
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000009:adverse effects / Q000097:blood* / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000097:blood / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D000078306:Clobazam; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D004148:Dioxolanes / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004831:Epilepsies, Myoclonic / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D005260:Female; D005632:Fructose / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D007223:Infant; D008297:Male; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D000077236:Topiramate; D014635:Valproic Acid / Q000009:adverse effects / Q000097:blood* / Q000627:therapeutic use*
chemical_list: D000927:Anticonvulsants; D004148:Dioxolanes; D000077236:Topiramate; D001569:Benzodiazepines; D000078306:Clobazam; D005632:Fructose; D014635:Valproic Acid; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; C021092:stiripentol
keywords: CYP2C19; Dravet syndrome; Stiripentol; Topiramate; Valproate