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

BMC Psychiatry

Kazuhiko Saito¹  Takuya Saito²  Takashi Okada³  Yushiro Yamashita⁴  Akemi Tomoda⁵  Hidetoshi Urano⁶  Hideo Umeuchi⁶  Akiko Mizuno-Yasuhira⁶  Saki Iwamori⁶  Satoru Shinoda⁶  Izumi Nishino⁶ 

[1] Aiiku Counselling Office, Aiiku Research Institute, Imperial Gift Foundation Boshi-Aiiku-Kai, Tokyo, Japan;Department of Child and Adolescent Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan;Department of Developmental Disorders, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan;Department of Child and Adolescent Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan;Department of Pediatrics and Child Health, Kurume University School of Medicine, Fukuoka, Japan;Research Center for Child Mental Development, University of Fukui, Fukui, Japan;Taisho Pharmaceutical Co., Ltd., Tokyo, Japan;

关键词: Drug repositioning;    TS-141;    ADHD;    CYP2D6 polymorphism;    Phenotype;    Clinical trial;    Tipepidine;   

DOI  :  10.1186/s12888-020-02932-2

来源: Springer

【 摘 要 】

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), https://www.clinicaltrials.jp/cti-user/trial/Show.jsp

【 授权许可】

CC BY