Evaluation of the Safety, Tolerability, and Pharmacokinetic Profiles of TP0473292 (TS-161), A Prodrug of a Novel Orthosteric mGlu2/3 Receptor Antagonist TP0178894, in Healthy Subjects and Its Antidepressant-Like Effects in Rodents

Abstract

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 of less than 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.

Investigational Drugs for the Treatment of Depression (Part 2): Glutamatergic, Cholinergic, Sestrin Modulators, and Other Agents

“…The blockade of metabotropic glutamate 2/3 (mGlu2/3) receptors is considered a potentially interesting approach in the treatment of MDD, based on several preclinical studies (Sanacora et al, 2008;Watanabe et al, 2021). TP0473292 (TS-161) is the prodrug of a novel mGlu2/3 receptor antagonist, investigated in trials for MDD treatment (Watanabe et al, 2021).…”

“…The blockade of metabotropic glutamate 2/3 (mGlu2/3) receptors is considered a potentially interesting approach in the treatment of MDD, based on several preclinical studies (Sanacora et al, 2008;Watanabe et al, 2021). TP0473292 (TS-161) is the prodrug of a novel mGlu2/3 receptor antagonist, investigated in trials for MDD treatment (Watanabe et al, 2021). In a first-in-human, randomized, double-blind, single ascending dose (15-400 mg) and 10-day-multiple-ascending dose (50-150 mg), phase I trial on healthy subjects (N = 70), the pharmacokinetic profile of TS-101 was described (Watanabe et al, 2021).…”

“…TP0473292 (TS-161) is the prodrug of a novel mGlu2/3 receptor antagonist, investigated in trials for MDD treatment (Watanabe et al, 2021). In a first-in-human, randomized, double-blind, single ascending dose (15-400 mg) and 10-day-multiple-ascending dose (50-150 mg), phase I trial on healthy subjects (N = 70), the pharmacokinetic profile of TS-101 was described (Watanabe et al, 2021). The prodrug was extensively converted into its active metabolite, and plasma exposure to this metabolite increased with the dose administered (Watanabe et al, 2021).…”

“…In a first-in-human, randomized, double-blind, single ascending dose (15-400 mg) and 10-day-multiple-ascending dose (50-150 mg), phase I trial on healthy subjects (N = 70), the pharmacokinetic profile of TS-101 was described (Watanabe et al, 2021). The prodrug was extensively converted into its active metabolite, and plasma exposure to this metabolite increased with the dose administered (Watanabe et al, 2021). The investigational product penetrated the brain-blood barrier, and the most frequently reported adverse events were nausea, vomiting, and dizziness, with an exposure-related incidence (Watanabe et al, 2021).…”

“…The prodrug was extensively converted into its active metabolite, and plasma exposure to this metabolite increased with the dose administered (Watanabe et al, 2021). The investigational product penetrated the brain-blood barrier, and the most frequently reported adverse events were nausea, vomiting, and dizziness, with an exposure-related incidence (Watanabe et al, 2021). An ongoing, placebo-controlled, phase II study is dedicated to the evaluation of TS-161 efficacy in TRD, with the main outcome being the change from baseline to day 21 on MADRS total scores and an estimated enrollment of 25 participants (NLM, NCT04821271).…”