title: Pharmacokinetics and tolerability of inhaled umeclidinium and vilanterol alone and in combination in healthy Chinese subjects: a randomized, open-label, crossover trial.
abstract: Inhaled umeclidinium (UMEC) and the combination of inhaled UMEC with vilanterol (UMEC/VI) are approved maintenance treatments for chronic obstructive pulmonary disease in the US and EU. This was a randomized, open-label, three-period crossover, single- and repeat-dose study to assess the pharmacokinetics (PK), safety, and tolerability of inhaled UMEC/VI 62.5/25 μg (delivering 55/22 μg) and UMEC/VI 125/25 μg (delivering 113/22 μg) compared with their monotherapy components (UMEC 62.5 μg, UMEC 125 μg and, VI 25 μg [delivering 55, 113, and 22 μg, respectively]) in healthy Chinese subjects (n=20). UMEC and VI were rapidly absorbed following single and repeat dosing (time to maximum plasma concentration [tmax]: UMEC = 5 min; VI = 5 min). The median tlast was 2–4 h for UMEC and 1–2 h for VI following single doses of UMEC/VI and UMEC monotherapy (both doses). UMEC reached steady-state prior to Day 10; steady-state for VI could not be assessed. UMEC accumulation following repeat dosing was 11–34% based on Cmax and 19–59% based on area under the concentration-time curve from time zero to 2 h (AUC(0-2)). VI accumulation following repeat dosing was 25–66% based on Cmax and 17–43% based on AUC(0-2). The evidence was not sufficient to suggest that systemic exposure was substantially different between UMEC/VI combination therapy and the constituent monotherapies following single or repeat dosing. Following both single- and repeat-dose administration, the inter-subject coefficient of variation for all UMEC PK parameter estimates ranged from 12% to 165% for all treatments, indicating a wide range of variability in inhaled PK parameters. Twelve subjects experienced ≥1 adverse event (AE). Six subjects experienced ≥1 treatment-related AE; the most commonly reported treatment-related AE was chest discomfort (n=3 [15%]). No clinically important changes in vital signs or electrocardiogram parameters were reported. These data suggest that single- and repeat-dose administration of UMEC/VI combination therapy in healthy Chinese subjects did not result in substantial differences in systemic exposure compared with UMEC and VI as monotherapies.
  
  
  BACKGROUND
  Clinicaltrials.gov NCT01899638 NCT01899638.
authors: Phase I Clinical Research Unit, Shanghai Xuhui Central Hospital, Shanghai, China.
authors: Chaoying
authors: C
authors: Hu
authors: Phase I Clinical Research Unit, Shanghai Xuhui Central Hospital, Shanghai, China.
authors: Jingying
authors: J
authors: Jia
authors: PTS China, GSK R&D, Shanghai, China.
authors: Kelly
authors: K
authors: Dong
authors: Statistics, Program and Data Management, GSK R&D, Shanghai, China.
authors: Linda
authors: L
authors: Luo
authors: Clinical Pharmacology Modelling & Simulation, GSK R&D, Shanghai, China.
authors: Kai
authors: K
authors: Wu
authors: Clinical Pharmacology Modelling & Simulation, GSK R&D, Research Triangle Park, NC, United States of America.
authors: Rashmi
authors: R
authors: Mehta
authors: Statistics, Program and Data Management, GSK R&D, Shanghai, China.
authors: Jack
authors: J
authors: Peng
authors: Clinical Pharmacology Modelling & Simulation, GSK R&D, Shanghai, China.
authors: Yan
authors: Y
authors: Ren
authors: Clinical Pharmacology Modelling & Simulation, GSK R&D, Ermington, Australia.
authors: Annette
authors: A
authors: Gross
authors: Clinical Medicine Development, GSK R&D, Shanghai, China.
authors: Hui
authors: H
authors: Yu
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D001592:Benzyl Alcohols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D002681:China; D002722:Chlorobenzenes / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy; D011812:Quinuclidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D001592:Benzyl Alcohols; D002722:Chlorobenzenes; C573971:GSK573719; D011812:Quinuclidines; C550468:vilanterol