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 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.