Cardiovascular safety profile of a fixed-dose combination of glycopyrrolate and formoterol fumarate delivered via metered dose inhaler using co-suspension delivery technology

Pulm Pharmacol Ther. 2018 Apr:49:67-74. doi: 10.1016/j.pupt.2018.01.007. Epub 2018 Feb 4.

Abstract

Background: Glycopyrrolate/formoterol fumarate (GFF) metered dose inhaler (MDI) is a fixed-dose combination of the long-acting muscarinic antagonist (LAMA), glycopyrrolate (GP), and the long-acting β2-agonist (LABA), formoterol fumarate (FF), delivered via metered dose inhaler using innovative co-suspension delivery technology. Here we report the results of two studies that examined the cardiovascular safety of GFF MDI.

Methods: The thorough QT (TQT) study was a Phase I, randomized, double-blind, single-dose, crossover study to assess GFF MDI 18/9.6 (Bevespi Aerosphere®), GFF MDI 144/38.4 and GP MDI 144 μg, compared with placebo MDI and open-label moxifloxacin 400 mg (active control) in healthy volunteers (PT003009). The cardiovascular safety study in patients with chronic obstructive pulmonary disease (COPD) was a Phase IIb, randomized, multicenter, double-blind, 14-day dosing, parallel-group study to evaluate GFF MDI 36/9.6, GP MDI 36 and FF MDI 9.6 μg compared with open-label FF dry powder inhaler (DPI; Foradil® Aerolizer®) 12 μg, in patients with moderate-to-severe COPD (PT003003 [NCT01349803]).

Results: Seventy healthy volunteers were randomized in the TQT study. GFF MDI 144/38.4, GFF MDI 18/9.6 and GP MDI 144 μg all met the confidence interval-based criteria for negative QT prolongation potential. In the study in patients with COPD, 237 subjects were randomized and treated. GFF MDI 36/9.6, GP MDI 36, and FF MDI 9.6 μg did not result in clinically meaningful changes from baseline in 24-h mean heart rate at Day 14 (primary endpoint) or in any of the other Holter monitoring endpoints at Day 14, compared with FF DPI 12 μg.

Conclusions: No clinically significant effects on cardiovascular safety occurred at therapeutic or supratherapeutic doses of GFF MDI, apart from a small and transient increase in heart rate following supratherapeutic dose of GFF MDI 144/38.4 μg. Furthermore, there were no unexpected safety findings reported in either healthy volunteers or patients with COPD.

Keywords: Bronchodilator agents; Chronic obstructive; Electrocardiography; GFF MDI; Holter monitoring; Pulmonary disease; QT prolongation.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Bronchodilator Agents / administration & dosage
  • Bronchodilator Agents / adverse effects
  • Cross-Over Studies
  • Double-Blind Method*
  • Drug Combinations
  • Drug Delivery Systems*
  • Female
  • Formoterol Fumarate / administration & dosage*
  • Formoterol Fumarate / adverse effects
  • Glycopyrrolate / administration & dosage*
  • Glycopyrrolate / adverse effects
  • Humans
  • Long QT Syndrome / etiology
  • Male
  • Metered Dose Inhalers
  • Middle Aged
  • Moxifloxacin / administration & dosage
  • Moxifloxacin / adverse effects
  • Muscarinic Antagonists / administration & dosage
  • Muscarinic Antagonists / adverse effects
  • Pulmonary Disease, Chronic Obstructive / drug therapy*
  • Pulmonary Disease, Chronic Obstructive / physiopathology
  • Technology, Pharmaceutical / methods
  • Young Adult

Substances

  • Bronchodilator Agents
  • Drug Combinations
  • Muscarinic Antagonists
  • Moxifloxacin
  • Glycopyrrolate
  • Formoterol Fumarate

Associated data

  • ClinicalTrials.gov/NCT01349803