Pharmacodynamics and Pharmacokinetics of @entity14680 / XXXX in Healthy Chinese Subjects.

@entity972 @entity16137 @entity565 @entity701 @entity14680 @entity1030
STUDY OBJECTIVE: To investigate the pharmacodynamic and pharmacokinetic profiles of @entity14680 (FF)/ @entity16137 (VI) - a fixed-dose combination of an inhaled corticosteroid (ICS) and a long-acting b2 -agonist for the treatment of @entity565 and @entity1030 - 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   g, 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 @entity701 level (ICSs), and increased Fridericia's corrected QT interval (QTcF) and reduced serum @entity972 level (long-acting b2 -agonists). Co-primary pharmacodynamic endpoints were 0-24-hour weighted mean serum @entity701 level on day 7 (cortisol0-24  hr, Day 7 ), and 0-4-hour weighted mean and maximum QTcF and weighted mean and minimum serum @entity972 level on days 1 and 7. @entity14680 and VI plasma concentrations, derived pharmacokinetic parameters, and safety were also assessed. Of the 16 subjects randomized, 15 completed the study. Reductions in @entity701 0-24  hour, Day 7 of 15% and 25% were observed with FF/VI 100/25 and 200/25   g, respectively, versus placebo. Minor increases (<  10  msec) in maximum QTcF on day 7 were seen with FF/VI 50/25 and 100/25   g but not with 200/25   g. Slight decreases in serum @entity972 level were only observed in subjects receiving FF/VI 50/25   g on day 1 and FF/VI 50/25 and 200/25   g on day 7. @entity14680 accumulation (day 7 vs day 1) for FF/VI 50/25-200/25   g ranged from 38 to 54% for maximum observed concentration and 63-71% for area under the concentration-time curve from 0 to 4  hours. @entity14680 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 b-adrenergic pharmacodynamic effects were observed with FF/VI doses ranging from 50/25 to 200/25   g. FF dose-dependent reductions in serum @entity701 levels of 15-25% were seen after administration of FF/VI 100/25 and 200/25   g. FF/VI was safe and well tolerated in these subjects at doses ranging from 50/25 to 200/25   g.
