Abstract

Study Objective To investigate the pharmacodynamic and pharmacokinetic profiles of fluticasone furoate (FF)/vilanterol (VI) – a fixed‐dose combination of an inhaled corticosteroid (ICS) and a long‐acting β2‐agonist for the treatment of asthma and chronic obstructive pulmonary disease – after single and repeat administration in healthy Chinese subjects. Design Double‐blind, placebo‐controlled, single‐site, randomized, four‐way crossover study. Setting The Clinical Pharmacological Research Centre at Peking Union Medical College Hospital [PUMCH]) in Beijing, China. Subjects Sixteen healthy, nonsmoking Chinese adults. Intervention Subjects were randomized to receive FF/VI 50/25, 100/25, or 200/25 μg, or placebo once/daily in the morning, delivered by the Ellipta dry powder inhaler, for 7 consecutive days. The subjects then received the other three treatments, with each treatment period separated by a 7‐day washout period. Measurements and Main Results The co‐primary outcome measures reflected pharmacodynamic responses relating to recognized class effects of the two drug classes: reduced serum cortisol level (ICSs), and increased Fridericia's corrected QT interval (QTcF) and reduced serum potassium level (long‐acting β2‐agonists). Co‐primary pharmacodynamic endpoints were 0–24‐hour weighted mean serum cortisol level on day 7 (cortisol0–24 hr, Day 7), and 0–4‐hour weighted mean and maximum QTcF and weighted mean and minimum serum potassium level on days 1 and 7. Fluticasone furoate and VI plasma concentrations, derived pharmacokinetic parameters, and safety were also assessed. Of the 16 subjects randomized, 15 completed the study. Reductions in cortisol0–24 hour, Day 7 of 15% and 25% were observed with FF/VI 100/25 and 200/25 μg, respectively, versus placebo. Minor increases (< 10 msec) in maximum QTcF on day 7 were seen with FF/VI 50/25 and 100/25 μg but not with 200/25 μg. Slight decreases in serum potassium level were only observed in subjects receiving FF/VI 50/25 μg on day 1 and FF/VI 50/25 and 200/25 μg on day 7. Fluticasone furoate accumulation (day 7 vs day 1) for FF/VI 50/25–200/25 μg ranged from 38 to 54% for maximum observed concentration and 63–71% for area under the concentration‐time curve from 0 to 4 hours. Fluticasone furoate pharmacokinetics were less than dose proportional. The VI pharmacokinetic profiles were similar for all three FF/VI doses. Adverse events were all mild in intensity and were reported by 13 (81%) of the 16 subjects. Conclusion In healthy Chinese subjects, minimal and non–clinically relevant β‐adrenergic pharmacodynamic effects were observed with FF/VI doses ranging from 50/25 to 200/25 μg. FF dose‐dependent reductions in serum cortisol levels of 15–25% were seen after administration of FF/VI 100/25 and 200/25 μg. FF/VI was safe and well tolerated in these subjects at doses ranging from 50/25 to 200/25 μg.