title: Pharmacodynamics and pharmacokinetics of fluticasone furoate/vilanterol in healthy Chinese subjects.
abstract: 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.
  
  
  METHODS
  Double-blind, placebo-controlled, single-site, randomized, four-way crossover study.
  
  
  METHODS
  The Clinical Pharmacological Research Centre at Peking Union Medical College Hospital [PUMCH]) in Beijing, China.
  
  
  METHODS
  Sixteen healthy, nonsmoking Chinese adults.
  
  
  METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Clinical Pharmacological Research Centre, Peking Union Medical College Hospital, Beijing, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Chen
authors.affiliation: Clinical Pharmacological Research Centre, Peking Union Medical College Hospital, Beijing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Clinical Pharmacological Research Centre, Peking Union Medical College Hospital, Beijing, China.
authors.forename: Ji
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Clinical Pharmacological Research Centre, Peking Union Medical College Hospital, Beijing, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Hu
authors.affiliation: GlaxoSmithKline (China) R&D Company, Shanghai, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Wu
authors.affiliation: GlaxoSmithKline (China) R&D Company, Shanghai, China.
authors.forename: Lihong
authors.initials: L
authors.lastname: Zhuang
authors.affiliation: GlaxoSmithKline (China) R&D Company, Shanghai, China.
authors.forename: Lian
authors.initials: L
authors.lastname: Liu
authors.affiliation: GlaxoSmithKline (China) R&D Company, Beijing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Du
authors.affiliation: Respiratory Medicines Development Centre, GlaxoSmithKline, Stevenage, Hertfordshire, UK.
authors.forename: Rodger
authors.initials: R
authors.lastname: Kempsford
authors.affiliation: Respiratory Medicines Development Centre, GlaxoSmithKline, Stevenage, Hertfordshire, UK.
authors.forename: Ann
authors.initials: A
authors.lastname: Allen
mesh_terms: D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000493:pharmacokinetics / Q000494:pharmacology*; D058666:Adrenergic beta-2 Receptor Agonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D000328:Adult; D000730:Androstadienes / Q000493:pharmacokinetics / Q000494:pharmacology*; D001592:Benzyl Alcohols / Q000493:pharmacokinetics / Q000494:pharmacology*; D002722:Chlorobenzenes / Q000493:pharmacokinetics / Q000494:pharmacology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008297:Male
chemical_list: D000305:Adrenal Cortex Hormones; D058666:Adrenergic beta-2 Receptor Agonists; D000730:Androstadienes; D001592:Benzyl Alcohols; D002722:Chlorobenzenes; D004338:Drug Combinations; C550468:vilanterol; C523187:fluticasone furoate
keywords: China; cortisol; fluticasone furoate, inhaled corticosteroids; long-acting beta2 agonists; pharmacodynamics; pharmacokinetics; systemic exposure; vilanterol