Methods: This was a single-center, placebo-controlled, randomized, double-blind phase 1 study. Japanese healthy male adult subjects were randomized into one of 5 cohorts, and received single oral dose of 6 mg, 20 mg, 40 mg, 60 mg, or 80 mg S-033188 suspension, or placebo in the fasted state. Signs and symptoms, treatment-emergent adverse events (TEAEs), and vital signs were assessed pre- and post-dosing. Blood and urine samples were also collected pre- and post-dosing and analyzed using liquid chromatography-tandem mass spectrometry.
Results: Forty subjects were randomized in this study (6 on S-033188 and 2 on placebo at each dose level). Plasma concentrations of S-033188 were below quantification limit (< 0.100 ng/mL) in almost all PK samples, suggesting that the pro-drug was effectively metabolized into the active form. S-033447 exposure (Cmax and AUC) increased in an almost dose-proportional manner in the dose range from 6-80 mg. The geometric mean t1/2,z of S-033447 ranged from 48.9 to 90.9 hours across dose groups and the geometric mean plasma S-033447 concentration at 24 hours post-dose was 6.92 ng/mL after administration of a 6 mg dose of S-033188. The geometric means of Feu0-72 of S-033447 ranged from 1.7% to 2.3%. One subject experienced a TEAE of headache, which was mild in severity and resolved without any treatments. No obvious trends were noted in other safety assessment.
Conclusion: Single oral doses of S-033188 at the doses of 6-80 mg were generally safe and well tolerated in healthy adult male subjects, and the active form S-033447 exhibits linear pharmacokinetics.
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