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Using the drug repositioning approach to develop a novel therapy, tipepidine hibenzate sustained-release tablet (TS-141), for children and adolescents with attention-deficit/hyperactivity disorder

  • Saito, Takuya1
  • Yamashita, Yushiro2
  • Tomoda, Akemi3
  • Okada, Takashi4, 5
  • Umeuchi, Hideo6
  • Iwamori, Saki6
  • Shinoda, Satoru6
  • Mizuno-Yasuhira, Akiko6
  • Urano, Hidetoshi6
  • Nishino, Izumi6
  • Saito, Kazuhiko7
  • 1 Hokkaido University Graduate School of Medicine, Sapporo, Japan , Sapporo (Japan)
  • 2 Kurume University School of Medicine, Fukuoka, Japan , Fukuoka (Japan)
  • 3 University of Fukui, Fukui, Japan , Fukui (Japan)
  • 4 National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan , Tokyo (Japan)
  • 5 Nagoya University Graduate School of Medicine, Nagoya, Japan , Nagoya (Japan)
  • 6 Taisho Pharmaceutical Co., Ltd., Tokyo, Japan , Tokyo (Japan)
  • 7 Aiiku Research Institute, Imperial Gift Foundation Boshi-Aiiku-Kai, Tokyo, Japan , Tokyo (Japan)
Published Article
BMC Psychiatry
Springer (Biomed Central Ltd.)
Publication Date
Nov 10, 2020
DOI: 10.1186/s12888-020-02932-2
Springer Nature


BackgroundAsverin® (tipepidine hibenzate) has been used as an antitussive for > 50 years in Japan. Studies revealed that tipepidine modulates monoamine levels, by inhibiting G-protein-activated inwardly rectifying potassium (GIRK) channels, expecting the potential therapeutic effects of tipepidine for attention-deficit/hyperactivity disorder (ADHD) in recent years. In this study, TS-141, a sustained-release tablet of tipepidine, was developed for the treatment of ADHD through a drug repositioning approach.MethodsThe sustained-release profile of TS-141 in healthy adults was investigated, and tipepidine exposure in the plasma after the TS-141 administration was compared to that of Asverin in the phase I study. Phase II study was conducted to examine the effects of TS-141 30 (once a day), 60 (once a day), 120 mg (60 mg twice a day), or placebo, that is within the exposure in the maximum dosage of Asverin, in children and adolescents with ADHD, and was designed as an 8-week treatment, randomized, parallel group, double-blind, placebo-controlled trial recruiting 6–17-year-old children and adolescents diagnosed with ADHD. A total of 216 patients were randomized according to the CYP2D6 phenotype. The primary end-point was ADHD Rating Scale IV-J changes. Furthermore, effects of CYP2D6 phenotype on the efficacy in the subgroup analysis were investigated.ResultsTS-141 had the sustained-release profile, and the CYP2D6 phenotype had effects on the plasma exposure of tipepidine. ADHD RS-IV-J scores in all TS-141 dosages decreased from their baseline scores; however, no significant difference was observed in ADHD RS-IV-J score changes between the placebo and TS-141-administered groups. In patients with intermediate metabolizer CYP2D6, ADHD RS-IV-J score changes in the 120 mg group tended to be larger than that in the placebo group.ConclusionsADHD RS-IV-J changes on TS-141 may depend on the interaction between the TS-141 dose and CYP2D6 phenotype, suggesting that further clinical trials should be conducted with careful consideration of polymorphism. Drug repositioning approach of TS-141 was attempted at the same dose as that of antitussive; however, dose setting according to the indication was necessary.Trial registrationPhase I study: JapicCTI-205235 (Registered 25 March 2020), Phase II study: JapicCTI-163244 (Registered 9 May 2016),

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