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 et al. BMC Psychiatry (2020) 20:530 https://doi.org/10.1186/s12888-020-02932-2 RESEARCH ARTICLE Open Access 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 Takuya Saito1, Yushiro Yamashita2, Akemi Tomoda3, Takashi Okada4,5, Hideo Umeuchi6, Saki Iwamori6* , Satoru Shinoda6, Akiko Mizuno-Yasuhira6, Hidetoshi Urano6, Izumi Nishino6 and Kazuhiko Saito7 Abstract Background: Asverin® (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. Methods: The 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. Results: TS-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. (Continued on next page) * Correspondence: 6 Taisho Pharmaceutical Co., Ltd., Tokyo, Japan Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Saito et al. BMC Psychiatry (2020) 20:530 Page 2 of 12 (Continued from previous page) Conclusions: ADHD 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 registration: Phase 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 Keywords: Drug repositioning, TS-141, ADHD, CYP2D6 polymorphism, Phenotype, Clinical trial, Tipepidine Background Drug repositioning/repurposing is defined as the strategy that employed existing compounds with the ultimate aim of successfully registering the drug for a new and potentially patentable indication [1]. Drug repositioning has attracted attention in recent years, and several advantages such as significant reduction of development costs, shortening of development period, and increased success probability were identified [2]. Asverin® (tipepidine hibenzate tablet) is a non-narcotic antitussive agent that has been widely used for > 50 years since its approval in 1959 in Japan and its safety in children and adolescents has already been established. Recently, tipepidine has been shown to attenuate the hyperactivity caused by neonatal 6-hydroxydopamine lesion, which is considered as an animal model of attention-deficit/hyperactivity disorder (ADHD) [3]. Several clinical open pilot studies have recently reported the effects of Asverin tablets for pediatric ADHD [4–6]. Thus, tipepidine is potentially useful as a therapeutic agent for pediatric ADHD. Since the half-life of Asverin is short, approximately 1.8 h in humans (Asverin package insert), leading to three doses a day and may be decreased in adherence for ADHD, we designed the slow release formulation of tipepidine in order to improve adherence to the treatment. ADHD is characterized by three main symptoms (inattention, hyperactivity, and impulsivity) and is classified as a neurodevelopmental disorder in DSM-5 [7]. In DSM-5, its prevalence has been reported to be 5% in children. According to a nationwide survey for teachers in Japan, the proportion of students who markedly show carelessness or hyperactivity-impulsiveness problems was 3.1% [8]. The quality of life (QOL) of patients with ADHD has been shown to decrease as the ADHD severity increased [9, 10]. Adults with ADHD have psychosocial impairment, poorer occupational performance, substance use, and traffic accidents [7]. Long-term follow-up clinical trials have reported that adult ADHD persistence is estimated approximately 1/ 3 to 2/3 of patients with ADHD in childhood [11, 12]. Early treatment of ADHD-related symptoms is important to improve the patient’s QOL [13]. Several drugs have already been approved for pediatric ADHD: central stimulants such as methylphenidate hydrochloride and lisdexamfetamine mesilate and nonstimulants such as atomoxetine hydrochloride, guanfacine hydrochloride, and clonidine hydrochloride. However, some concerns on potential long-term effects of stimulant ADHD medications were found on the patients’ growth and weight, (...truncated)