A phase 1 study of safety, tolerability and pharmacokinetics of oral single-dose S-033188, a novel anti-influenza agent, in healthy adult male subjects

BACKGROUND: Cap‐dependent endonuclease (CEN) activity of the influenza poly‐merase is essential for the "cap‐snatching" process during influenza viral transcription. S‐033188 is a novel, selective inhibitor of CEN with potent antiviral activity against Type A and Type B influenza virus in vitro and in vivo. The aim of this study is to determine safety and tolerability of single ascending doses of S‐033188, and pharma‐cokinetics of both the pro‐drug form S‐033188 and the active form S‐033447 in healthy adult male subjects. METHODS: This was a single‐center, placebo‐controlled, randomized, double‐blind phase 1 study. Japanese healthy male adult subjects were randomized into 1 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.