Background TP0473292 (the active ingredient of TS-161) is a prodrug of a novel metabotropic glutamate (mGlu) 2/3 receptor antagonist being developed for the treatment of patients with depression. This study evaluated the safety, tolerability, and pharmacokinetics of orally administered TS-161 in healthy subjects. Methods This was a first-in-human, phase 1, randomized, double-blind, placebo-controlled, single-ascending dose (15–400 mg TS-161) and 10-day multiple-ascending dose (50–150 mg TS-161) study in healthy subjects, conducted from June 2019 through February 2020. Plasma and urine concentrations of the prodrug and its metabolites, and cerebrospinal fluid (CSF) concentrations of the active metabolite TP0178894 were measured to evaluate the pharmacokinetic profiles after oral administration of TS-161. Results Following single and multiple doses, TP0473292 was extensively converted into its active metabolite TP0178894. Plasma concentrations of TP0178894 reached peak (Cmax) within 5 hours post dose and declined with a t1/2 <13 hours. Plasma exposures of TP0178894 increased with increasing dose. TP0178894 penetrated into CSF and reached a Cmax of 9.892 ng/mL at a single dose of 100 mg, which was comparable with IC50 values of antagonist activity at mGlu2/3 receptors. The most frequently observed adverse events that showed exposure-related incidence during the study were nausea, vomiting, and dizziness. Conclusions The mGlu2/3 receptor antagonist prodrug TP0473292 is safe and well-tolerated, is orally bioavailable in humans with extensive conversion into the active metabolite TP0178894 with sufficient CSF penetration to exert the anticipated pharmacological effects, and is a promising candidate for further clinical development in treatment of patients with depression.

中文翻译：

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TP0473292 (TS-161)（一种新型正构 mGlu2/3 受体拮抗剂 TP0178894 的前药）在健康受试者中的安全性、耐受性和药代动力学特征及其在啮齿动物中的抗抑郁样作用的评估

背景 TP0473292（TS-161 的活性成分）是一种新型代谢型谷氨酸 (mGlu) 2/3 受体拮抗剂的前药，正在开发用于治疗抑郁症患者。本研究评估了健康受试者口服 TS-161 的安全性、耐受性和药代动力学。方法 这是首次人体试验、1 期、随机、双盲、安慰剂对照、单次递增剂量（15-400 mg TS-161）和 10 天多次递增剂量（50-150 mg TS -161) 于 2019 年 6 月至 2020 年 2 月在健康受试者中进行的研究。测量了前药及其代谢物的血浆和尿液浓度，以及活性代谢物 TP0178894 的脑脊液 (CSF) 浓度，以评估口服给药后的药代动力学特征TS-161。结果 单次和多次给药后，TP0473292 被广泛转化为其活性代谢物 TP0178894。TP0178894 的血浆浓度在给药后 5 小时内达到峰值 (Cmax)，并随着 t1/2 ＜13 小时下降。TP0178894 的血浆暴露随着剂量的增加而增加。TP0178894 渗透到 CSF 中，在 100 mg 的单剂量下达到 9.892 ng/mL 的 Cmax，这与 mGlu2/3 受体拮抗剂活性的 IC50 值相当。研究期间最常观察到的与暴露相关的不良事件是恶心、呕吐和头晕。结论 mGlu2/3 受体拮抗剂前药 TP0473292 安全且耐受性良好，在人体中具有口服生物利用度，可广泛转化为活性代谢物 TP0178894，并具有足够的 CSF 渗透以发挥预期的药理作用，