Safety and Pharmacokinetic Profiles of MGS0274 Besylate (TS-134), a Novel Metabotropic Glutamate 2/3 Receptor Agonist Prodrug, in Healthy Subjects.

AIMS: The safety and pharmacokinetics of single and multiple doses of a novel mGlu2/3 receptor agonist prodrug, MGS0274 besylate (TS-134), were investigated in healthy subjects. METHODS: Phase 1 single-ascending dose (SAD; 5-20 mg) and multiple-ascending dose titration (MAD; 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 SAD study (10 mg), concentrations of MGS0008, the active compound, in the cerebrospinal fluid (CSF) were measured for up to 24 h post-dose. RESULTS: Following single and multiple oral administrations, MGS0274 was rapidly absorbed and extensively converted into MGS0008, which reached a maximum concentration (Cmax ) in plasma within 4 h post-dose and declined with a terminal half-life (t1/2 ) of around 10 h. Plasma exposure to MGS0274 was minimal, accounting for approximately 3% of the area under the concentration-time curve (AUC) of MGS0008. Plasma Cmax and AUC of MGS0008 at steady state increased dose proportionally (5-80 mg). MGS0008 penetrated into CSF, with a CSF-to-plasma Cmax ratio of 3.66%, and was eliminated with a t1/2 of approximately 16 h. The most frequent treatment-emergent adverse events observed following single and multiple oral administration included headache, nausea, somnolence, dizziness and vomiting. CONCLUSIONS: 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.