title: Dose response of umeclidinium administered once or twice daily in patients with COPD: a randomised cross-over study.
abstract: BACKGROUND
  Umeclidinium bromide (UMEC) is an inhaled long-acting muscarinic antagonist in development for chronic obstructive pulmonary disease (COPD).
  
  
  METHODS
  This was a multicentre, randomised, double-blind, placebo-controlled, three-way cross-over, incomplete block study to evaluate UMEC 15.6, 31.25, 62.5, and 125 μg administered once daily (QD), and UMEC 15.6 μg and 31.25 μg administered twice daily (BID), over 7 days in patients with COPD. Tiotropium was included as an open-label treatment arm. The primary efficacy endpoint was trough forced expiratory volume in 1 second (FEV1) on Day 8. Secondary efficacy endpoints included weighted mean FEV1 over 0-24 hours after morning dosing on Day 7, and serial FEV1 at each time point over 24 hours after morning dosing on Day 7. Safety and pharmacokinetics were also examined.
  
  
  RESULTS
  One hundred and sixty-three patients (mean age 59.5 years, 52% female) were randomised. Based on the population dose-response model of trough FEV1 data, the geometric mean potency (ED50) of UMEC was 37 μg (95% confidence interval [CI]: 18, 57) with a predicted maximum intrinsic efficacy (Emax) at trough of 0.185 L (95% CI: 0.153, 0.218) after QD dosing. UMEC 125 μg QD demonstrated the greatest improvements in measure of lung function compared with doses of 62.5 μg and below. UMEC 125 μg QD exhibited more consistent increases in FEV1 from baseline across serial time points over 24 hours compared with other UMEC doses and tiotropium. Increases in FEV1 over 0-12 hours were similar to those observed over 12-24 hours after the second dose of UMEC was administered. UMEC was rapidly absorbed following inhaled dosing and eliminated from plasma. Adverse events, generally mild, were highest with UMEC 125 μg QD (18%) compared with placebo (8%), tiotropium (4%) and other UMEC doses (5-12%).
  
  
  CONCLUSIONS
  UMEC is a potent QD bronchodilator with geometric mean ED50 of 37 μg. A dose ordering over the range of UMEC 15.6-125 μg QD doses was observed, with UMEC 125 μg showing the greatest improvement in trough FEV1.
authors.forename: Alison
authors.initials: A
authors.lastname: Church
authors.affiliation: Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Stevenage SG1 2NY, UK. misba.2.beerahee@gsk.com.
authors.forename: Misba
authors.initials: M
authors.lastname: Beerahee
authors.forename: Jean
authors.initials: J
authors.lastname: Brooks
authors.forename: Rashmi
authors.initials: R
authors.lastname: Mehta
authors.forename: Palvi
authors.initials: P
authors.lastname: Shah
mesh_terms: D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage* / Q000494:pharmacology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000503:physiopathology; D011812:Quinuclidines / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: C573971:GSK573719; D018727:Muscarinic Antagonists; D011812:Quinuclidines