Objective: To evaluate the safety, pharmacokinetics and pharmacodynamics of fluticasone furoate (FF) and vilanterol (VI) administered alone or in combination in three Phase I studies in healthy Japanese male subjects.
Materials: FF, VI and FF/VI inhalation powder in a novel dry powder inhaler (nDPI).
Methods: Study A: 48 subjects received the first dose on Day 1, followed by a 4-day washout and once-daily (OD) repeat doses of FF 200, 400 or 800 μg or placebo from Day 5 to Day 11 (7 days). Study B: 32 subjects received repeat doses of VI (12.5, 25 μg) OD for 7 days. Study C: 16 subjects received single doses of FF (800 μg), VI (50 μg), FF/VI (800/50 μg) and placebo.
Results: Overall, there were no safety concerns and no major differences were found in treatment-related adverse events when FF and VI were administered alone or in combination. Peak plasma concentration of FF and VI following repeat dosing was up to two times higher compared with the single dose. Individual pharmacokinetic parameters of FF and VI differed when co-administered but the differences from monotherapy were not clinically significant. Repeat dosing of FF affected weighted mean (0 - 24 hours) serum cortisol with FF 200, 400 and 800 μg resulting in respective reductions from placebo of 32%, 38% and 97%, respectively. Mean maximum heart rate (0 - 4 hours) was comparable between placebo, VI 12.5 and 25 μg over 7 days of dosing; for single dosing of FF/VI 800/50 and VI 50 μg, heart rate was comparable (70 and 73 bpm, respectively) and this was higher than FF 800 μg (66 bpm) or placebo (64 bpm), but the difference was not clinically significant.
Conclusions: In healthy Japanese subjects, no safety concerns were found following repeat dosing of FF and VI or single dosing of FF, VI and FF/VI. Systemic exposure to FF and VI increased in a dose-dependent manner. Serum cortisol level was suppressed by 97% after 7 days repeat administration of FF at a dose of 800 μg. Heart rate with a single dose of VI 50 μg was higher than that of placebo, though not to a clinically significant extent.