TP0473292 (the active component in TS-161) is a prodrug of new metabotropic glutamate (mGlu) 2/3 receptor antagonist that was being investigated for the treatment of depression patients. The safety, tolerability, and pharmacokinetics of orally given TS-161 in healthy people were investigated by the researchers for a study. From June 2019 to February 2020, it 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) research in healthy participants. To assess the pharmacokinetic characteristics of TS-161, plasma and urine concentrations of the prodrug and its metabolites, as well as cerebrospinal fluid (CSF) concentrations of the active metabolite TP0178894, were examined.

TP0473292 was significantly transformed into its active metabolite TP0178894 after single and repeated doses. TP0473292 was significantly transformed into its active metabolite TP0178894 after single and repeated doses. TP0178894 plasma concentrations peaked (Cmax) 5 hours after administration and thereafter dropped with a t1/2 of fewer than 13 hours. The plasma concentrations of TP0178894 rose with increasing dosage. At a single dosage of 100 mg, TP0178894 entered CSF and achieved a Cmax of 9.892 ng/mL, which was equivalent to the IC50 values of antagonist action at mGlu2/3 receptors. During the trial, the most commonly seen adverse effects that exhibited exposure-related incidence were nausea, vomiting, and dizziness.

The mGlu2/3 receptor antagonist prodrug TP0473292 was safe and well-tolerated in humans, was orally bioavailable in humans with extensive conversion to the active metabolite TP0178894 and sufficient CSF penetration to exert the expected pharmacological effects and was a promising candidate for further clinical development in the treatment of patients with depression.

Reference:academic.oup.com/ijnp/article/25/2/106/6371845