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. 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. 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. 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. 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

中文翻译：

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使用药物重新定位方法开发一种新的疗法，替匹定hibenzate缓释片（TS-141），用于患有注意力缺陷/多动症的儿童和青少年

在日本，Asverin®（替苯哌丁酯）已用作镇咳药已有50多年的历史了。研究表明，替匹定通过抑制G蛋白激活的内向整流钾（GIRK）通道来调节单胺水平，并期望近年来替匹定对注意力缺乏/多动症（ADHD）的潜在治疗作用。在这项研究中，开发了TS-141，一种替匹定的缓释片剂，通过药物重新定位方法来治疗ADHD。研究了健康成年人体内TS-141的缓释曲线，并在I期研究中比较了TS-141给药后血浆中的阿替匹定暴露量与Asverin的暴露情况。进行了II期研究，以检查TS-141 30（一天一次），60（一天一次），120 mg（一天两次60 mg）或安慰剂的作用，在患有ADHD的儿童和青少年中，在Asverin的最大剂量暴露范围内，并且设计为8周治疗，随机，平行组，双盲，安慰剂对照试验，招募6-17岁的儿童被诊断患有多动症的儿童和青少年。共有216例患者根据CYP2D6表型随机分组。主要终点是ADHD评分量表IV-J的变化。此外，研究了CYP2D6表型对亚组分析疗效的影响。TS-141具有持续释放特性，CYP2D6表型对替匹定的血浆暴露有影响。所有TS-141剂量的ADHD RS-IV-J得分均低于其基线得分；然而，在安慰剂组和TS-141给药组之间的ADHD RS-IV-J得分变化中未观察到显着差异。在具有中间代谢物CYP2D6的患者中，120 mg组的ADHD RS-IV-J评分变化倾向于大于安慰剂组。TS-141上的ADHD RS-IV-J的变化可能取决于TS-141剂量与CYP2D6表型之间的相互作用，提示应进行进一步的临床试验，并仔细考虑其多态性。尝试以与镇咳药相同的剂量使用TS-141进行药物重新定位。但是，必须根据适应症设定剂量。第一阶段研究：JapicCTI-205235（于2020年3月25日注册），第二阶段研究：JapicCTI-163244（于2016年5月9日注册），https://www.clinicaltrials.jp/cti-user/trial/Show.jsp TS-141上的ADHD RS-IV-J的变化可能取决于TS-141剂量与CYP2D6表型之间的相互作用，提示应进行进一步的临床试验，并仔细考虑其多态性。尝试以与镇咳药相同的剂量使用TS-141进行药物重新定位。但是，必须根据适应症设定剂量。第一阶段研究：JapicCTI-205235（于2020年3月25日注册），第二阶段研究：JapicCTI-163244（于2016年5月9日注册），https://www.clinicaltrials.jp/cti-user/trial/Show.jsp TS-141上的ADHD RS-IV-J的变化可能取决于TS-141剂量与CYP2D6表型之间的相互作用，提示应进行进一步的临床试验，并仔细考虑其多态性。尝试以与镇咳药相同的剂量使用TS-141进行药物重新定位。但是，必须根据适应症设定剂量。第一阶段研究：JapicCTI-205235（于2020年3月25日注册），第二阶段研究：JapicCTI-163244（于2016年5月9日注册），https://www.clinicaltrials.jp/cti-user/trial/Show.jsp 必须根据适应症设定剂量。第一阶段研究：JapicCTI-205235（于2020年3月25日注册），第二阶段研究：JapicCTI-163244（于2016年5月9日注册），https://www.clinicaltrials.jp/cti-user/trial/Show.jsp 必须根据适应症设定剂量。第一阶段研究：JapicCTI-205235（于2020年3月25日注册），第二阶段研究：JapicCTI-163244（于2016年5月9日注册），https://www.clinicaltrials.jp/cti-user/trial/Show.jsp