title: Efficacy and safety of nebulized glycopyrrolate for administration using a high efficiency nebulizer in patients with chronic obstructive pulmonary disease.
abstract: OBJECTIVE
  To establish the dose-response for pharmacodynamics (bronchodilatation), safety and pharmacokinetics for a nebulized formulation of the long acting muscarinic antagonist glycopyrrolate (EP-101) with a high efficiency nebulizer in patients with chronic obstructive pulmonary disease (COPD).
  
  
  METHODS
  Patients with moderate to severe COPD (GOLD II/III), with reversible lung function, were enrolled into this randomized, double-blind, placebo-controlled, six period crossover study (n = 42). Patients received single doses of EP-101 (12.5-400 μg) and placebo via a high efficiency nebulizer (eFlow® PARI nebulizer), with washout between treatments. Plasma pharmacokinetics were assessed in a subset of patients (n = 11).
  
  
  RESULTS
  All treatments were well tolerated with similar adverse event rates reported with placebo and at all doses. There were no clinically relevant changes in heart rate, systolic and diastolic blood pressure or in ECG parameters including QTc interval. Following treatment with EP-101 at all doses there was a rapid bronchodilator response within 5 min. Significant improvements in mean change from baseline FEV1 at 24 h were reported at doses ≥ 50 μg compared with placebo, with a clear dose-response relationship. Mean changes in FEV1 were 0.10 l (95% CI 0.06, 0.14) and 0.12 l (95% CI 0.08, 0.16) for 100 μg and 200 μg, respectively.
  
  
  CONCLUSIONS
  Single doses of EP-101 ranging from 12.5 μg to 400 μg were well tolerated. EP-101 delivered by high efficiency nebulizer device produced a rapid onset of bronchodilatation with clinically meaningful improvements in lung function maintained over a 24 h period at all doses >50 μg.
authors.affiliation: Respiratory Clinical Trials Ltd, London, UK.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Leaker
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Barnes
authors.forename: C Richard
authors.initials: CR
authors.lastname: Jones
authors.forename: Ahmet
authors.initials: A
authors.lastname: Tutuncu
authors.forename: Dave
authors.initials: D
authors.lastname: Singh
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D000368:Aged; D001794:Blood Pressure / Q000187:drug effects; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004867:Equipment Design; D005260:Female; D006024:Glycopyrrolate / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D009330:Nebulizers and Vaporizers; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D012129:Respiratory Function Tests; D012720:Severity of Illness Index
chemical_list: D001993:Bronchodilator Agents; D018727:Muscarinic Antagonists; D006024:Glycopyrrolate
keywords: COPD; EP-101; LAMA; glycopyrrolate; muscarinic antagonist; nebulizer