Preclinical metabolism and the disposition of vornorexant/TS‐142, a novel dual orexin 1/2 receptor antagonist for the treatment of insomnia,Pharmacology Research & Perspectives

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Preclinical metabolism and the disposition of vornorexant/TS‐142, a novel dual orexin 1/2 receptor antagonist for the treatment of insomnia
Pharmacology Research & Perspectives ( IF 2.9 ) Pub Date : 2024-03-16 , DOI: 10.1002/prp2.1183
Yoshihiro Konno ₁ , Shunsuke Kamigaso ₁ , Hidetoh Toki ₁ , Shuichi Terasaka ₁ , Hirohiko Hikichi ₂ , Hiromi Endo ₁ , Jun-Ichi Yamaguchi ₁ , Akiko Mizuno-Yasuhira ₁

Affiliation

We investigated the metabolism and disposition of vornorexant, a novel dual orexin receptor antagonist, in rats and dogs, and clarified in vitro metabolite profiles in humans. Furthermore, we investigated the pharmacokinetics of active metabolites in rats and dogs and their CNS distribution in rats to elucidate its contribution to drug efficacy. [14C]vornorexant was rapidly and mostly absorbed after the oral administration in rats and dogs. The drug‐derived radioactivity, including metabolites, was distributed to major organs such as the liver, kidneys in rats, and was almost eliminated within 24 h post‐dose in both species. Metabolite profiling revealed that main clearance mechanism of vornorexant was metabolism via multiple pathways by oxidation. The major circulating components were the cleaved metabolites (M10, M12) in rats, and the unchanged form in dogs, followed by M1, and then M3. Incubation with human hepatocytes resulted in formation of metabolites, including M1, M3, M10, and M12. The metabolic pathways were similar in all tested species. Resulting from the PK and CNS distribution of active metabolites (M1 and M3) with weaker pharmacological activity, the concentration of the unchanged form was higher than that of active metabolites in rat CSF and dog plasma, suggesting that the unchanged form mainly contributed to the drug efficacy. These findings demonstrate that vornorexant is absorbed immediately after administration, and vornorexant and its metabolites are rapidly and completely eliminated in rats and dogs. Thus, vornorexant may have favorable pharmacokinetic profiles as a hypnotic drug to provide rapid onset of action and minimal next‐day residual effects in humans.

中文翻译：

vornorexant/TS-142 的临床前代谢和处置，vornorexant/TS-142 是一种用于治疗失眠的新型双重食欲素 1/2 受体拮抗剂

我们研究了新型双食欲素受体拮抗剂 vornorexant 在大鼠和狗体内的代谢和处置，并阐明了人类的体外代谢物谱。此外，我们研究了活性代谢物在大鼠和狗体内的药代动力学及其在大鼠体内的 CNS 分布，以阐明其对药物疗效的贡献。[14C]vornorexant 在大鼠和狗口服给药后迅速且大部分被吸收。药物衍生的放射性，包括代谢物，分布在大鼠的肝脏、肾脏等主要器官，并且在两个物种的给药后 24 小时内几乎被消除。代谢物分析显示，vornorexant 的主要清除机制是通过多种途径通过氧化进行代谢。主要循环成分是大鼠裂解的代谢物（M10、M12）和狗的不变形式，其次是 M1，然后是 M3。与人肝细胞孵育导致代谢物的形成，包括 M1、M3、M10 和 M12。所有测试物种的代谢途径都相似。由于药理活性较弱的活性代谢物（M1 和 M3）的 PK 和 CNS 分布，未改变形式在大鼠 CSF 和狗血浆中的浓度高于活性代谢物，表明未改变形式主要有助于药物疗效。这些发现表明，vornorexant 在给药后立即被吸收，并且 vornorexant 及其代谢物在大鼠和狗体内被迅速完全消除。因此，vornorexant 作为催眠药物可能具有良好的药代动力学特征，可在人体中提供快速起效和最小的次日残留效应。

更新日期：2024-03-16

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