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
| Autor: | Mai Watanabe, Michihiko Iijima, Hirotaka Watase, Toshiyuki Marumo, Carlos A. Zarate, Brian Marcy, Ayano Hiroki, Kohnosuke Kinoshita, Shigeyuki Chaki |
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| Rok vydání: | 2021 |
| Předmět: |
Adult
Male Adolescent medicine.drug_class Cmax Administration Oral Rodentia Pharmacology Receptors Metabotropic Glutamate Young Adult Pharmacokinetics Double-Blind Method Oral administration medicine Animals Humans Pharmacology (medical) Prodrugs Active metabolite Dose-Response Relationship Drug business.industry Depression Antagonist Prodrug Middle Aged Receptor antagonist Antidepressive Agents Psychiatry and Mental health Tolerability Area Under Curve Female business |
| Zdroj: | The international journal of neuropsychopharmacology. 25(2) |
| ISSN: | 1469-5111 |
| Popis: | 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 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. |
| Databáze: | OpenAIRE |
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