The safety, pharmacokinetics and pharmacodynamics of a combination of fluticasone furoate and vilanterol in healthy Japanese subjects

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 mu g or placebo from Day 5 to Day 11 (7 days). Study B: 32 subjects received repeat doses of VI (12.5, 25 mu g) OD for 7 days. Study C: 16 subjects received single doses of FF (800 mu g), VI (50 mu g), FF/VI (800/50 mu g) 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. Teak plasma concentration of FF and VI following repeat dosing was up to 2 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 mu g 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 mu g over 7 days of dosing; for single dosing of FF/VI 800/50 and VI 50 mu g, heart rate was comparable (70 and 73 bpm, respectively) and this was higher than FF 800 mu g (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 mu g. Heart rate with a single dose of VI 50 mu g was higher than that of placebo, though not to a clinically significant extent.