title: Randomized study of the safety, pharmacokinetics, and bronchodilatory efficacy of a proprietary glycopyrronium metered-dose inhaler in study patients with chronic obstructive pulmonary disease.
abstract: BACKGROUND
  Bronchodilator medications are central to the symptomatic management of chronic obstructive pulmonary disease (COPD). Metered-dose inhalers (MDIs) are the most commonly used devices to deliver treatment to patients with COPD and asthma, comprising approximately 70% of bronchodilator prescriptions. Proprietary porous-particle technology permits the formulation of long-acting muscarinic antagonists, long-acting β2-agonists, and a combination of both in hydrofluoroalkane (HFA) MDIs, providing a solution to formulation challenges inherent to the development of HFA MDIs, which have contributed to the development of dry-powder inhalers.
  
  
  METHODS
  In this randomized, double-blind, 4-period, 6-treatment, placebo- and active-controlled, multicenter, crossover study, 4 ascending single doses of a proprietary glycopyrronium (GP) MDI were evaluated compared with Placebo MDI and open-label tiotropium (TIO) in study patients with COPD. Thirty-three study patients were enrolled and received single-dose administration of 4 of the 6 treatments (Placebo MDI, TIO 18 μg, or GP MDI at 14.4, 28.8, 57.6, and 115.2 μg ex-actuator) with an interval of 1 to 3 weeks between doses. The primary efficacy endpoint was peak change in forced expiratory volume in 1 second (FEV1).
  
  
  RESULTS
  All 4 doses of GP MDI showed statistically superior efficacy compared with Placebo MDI for peak FEV1 (differences of 146 to 248 mL; P<.001), with a clear dose ordering of the response. Statistically significant differences compared with Placebo MDI were noted at almost all doses for the secondary FEV1 parameters (P ≤ .049) except 24-hour trough FEV1 at 28.8 μg. All doses were safe and well tolerated in this study; the most frequently reported adverse event was dry mouth (0-14.3% across doses; 9.5% for Placebo MDI, and 9.1% for TIO).
  
  
  CONCLUSIONS
  This study demonstrated superior bronchodilatory efficacy of GP MDI compared with Placebo MDI at all doses tested, and no serious adverse events were reported. This study supports the further evaluation of GP MDI in study patients with COPD. In addition, these findings indicate that the correct dosage of glycopyrronium is no more than 115.2 μg total daily dose, or 57.6 μg twice daily based on comparisons with the active comparator.
  
  
  BACKGROUND
  This clinical trial was registered on ClinicalTrials.gov, Identifier: NCT00871182.
authors.affiliation: University of Nebraska Medical Center, Physicians Internal Medicine at the Durham Outsubject Center, Omaha, NE, USA. srennard@unmc.edu.
authors.forename: Stephen
authors.initials: S
authors.lastname: Rennard
authors.forename: Charles
authors.initials: C
authors.lastname: Fogarty
authors.forename: Colin
authors.initials: C
authors.lastname: Reisner
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernandez
authors.forename: Tracy
authors.initials: T
authors.lastname: Fischer
authors.forename: Michael
authors.initials: M
authors.lastname: Golden
authors.forename: Earl St
authors.initials: ES
authors.lastname: Rose
authors.forename: Patrick
authors.initials: P
authors.lastname: Darken
authors.forename: Gregory
authors.initials: G
authors.lastname: Tardie
authors.forename: Chadwick
authors.initials: C
authors.lastname: Orevillo
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001993:Bronchodilator Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume; D006024:Glycopyrrolate / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D036501:Metered Dose Inhalers; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D012602:Scopolamine Derivatives / Q000627:therapeutic use; D000069447:Tiotropium Bromide; D014987:Xerostomia / Q000139:chemically induced
chemical_list: D001993:Bronchodilator Agents; D018727:Muscarinic Antagonists; D012602:Scopolamine Derivatives; D006024:Glycopyrrolate; D000069447:Tiotropium Bromide