Watanabe_2020_Br.J.Clin.Pharmacol_86_2286

AIMS: The safety and pharmacokinetics of single and multiple doses of a novel mGlu(2/3) receptor agonist prodrug, MGS0274 besylate (TS-134), were investigated in healthy subjects. METHODS: Phase 1 single-ascending dose (5-20 mg) and multiple-ascending dose titration (5-80 mg) studies were conducted in healthy male and female subjects. Both studies were randomized, double-blinded and placebo-controlled. In one cohort of single-ascending dose study (10 mg), concentrations of MGS0008, the active compound, in the cerebrospinal fluid (CSF) were measured for up to 24 hours postdose. RESULTS: Following single and multiple oral administrations, MGS0274 was rapidly absorbed and extensively converted into MGS0008, which reached a maximum concentration (C(max) ) in plasma within 4 hours postdose and declined with a terminal half-life (t(1/2) ) of around 10 hours. Plasma exposure to MGS0274 was minimal, accounting for approximately 3% of the area under the concentration-time curve (AUC) of MGS0008. Plasma C(max) and AUC of MGS0008 at steady state increased dose proportionally (5-80 mg). MGS0008 penetrated into CSF, with a CSF-to-plasma C(max) ratio of 3.66%, and was eliminated with a t(1/2) of approximately 16 hours. The most frequent treatment-emergent adverse events observed following single and multiple oral administration included headache, nausea, somnolence, dizziness and vomiting. CONCLUSION: TS-134 is orally bioavailable in humans and converts rapidly and extensively to MGS0008, which exhibits good CSF penetration. Orally administered TS-134 was safe and generally well-tolerated; hence, TS-134 is a promising candidate for further clinical development for the treatment of disorders in which glutamatergic abnormalities are involved, such as schizophrenia.