Department of Child and Adolescent Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Department of Pediatrics and Child Health, Kurume University School of Medicine, Fukuoka, Japan.
BMC Psychiatry. 2020 Nov 10;20(1):530. doi: 10.1186/s12888-020-02932-2.
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.
Asverin®（盐酸替哌啶）在日本已作为镇咳药使用超过 50 年。研究表明，替哌啶通过抑制 G 蛋白激活内向整流钾（GIRK）通道来调节单胺水平，近年来人们期望替哌啶对注意缺陷/多动障碍（ADHD）有潜在的治疗作用。在这项研究中，通过药物重新定位方法开发了替哌啶的缓释片 TS-141，用于治疗 ADHD。
研究了健康成年人中 TS-141 的缓释特征，并比较了 TS-141 给药后血浆中的替哌啶暴露与 I 期研究中 Asverin 的暴露。进行了 II 期研究，以检查 TS-141 30（每天一次）、60（每天一次）、120mg（每天两次 60mg）或安慰剂在 ADHD 儿童和青少年中的作用，该剂量在 Asverin 的最大剂量范围内，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 岁诊断为 ADHD 的儿童和青少年。共有 216 名患者根据 CYP2D6 表型进行了随机分组。主要终点为 ADHD 评定量表 IV-J 的变化。此外，还研究了 CYP2D6 表型对亚组分析中疗效的影响。
TS-141 具有缓释特征，CYP2D6 表型对替哌啶的血浆暴露有影响。所有 TS-141 剂量的 ADHD RS-IV-J 评分均从基线评分下降；然而，安慰剂组和 TS-141 给药组之间 ADHD RS-IV-J 评分变化无显著性差异。在中间代谢 CYP2D6 的患者中，120mg 组的 ADHD RS-IV-J 评分变化趋势大于安慰剂组。
TS-141 的 ADHD RS-IV-J 变化可能取决于 TS-141 剂量与 CYP2D6 表型之间的相互作用，表明应在充分考虑多态性的情况下进行进一步的临床试验。TS-141 的药物再定位方法采用了与镇咳药相同的剂量；然而，根据适应症设定剂量是必要的。
I 期研究：JapicCTI-205235（2020 年 3 月 25 日注册），II 期研究：JapicCTI-163244（2016 年 5 月 9 日注册），https://www.clinicaltrials.jp/cti-user/trial/Show.jsp。
