Efficacy and safety of nebulized glycopyrrolate for administration using a high efficiency nebulizer in patients with chronic obstructive pulmonary disease

Abstract

Aims: 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.

Conclusion: 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.

Keywords: COPD; EP-101; LAMA; glycopyrrolate; muscarinic antagonist; nebulizer.

© 2014 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

Figures

Figure 1

A schematic of the aerosol production within the eFlow® nebulizer system

Figure 2

Mean change from baseline FEV1 after different doses of nebulized glycopyrrolate. The first assessment at 5 min post-dose is displayed at 0 h. , placebo; , 12.5 μg; , 50 μg; , 100 μg; , 200 μg; , 400 μg

Figure 3

Standardized (time normalized) FEV1 (0–24 h) (ITT population; mean ± SEM). n = 37–39

Figure 4

Placebo-adjusted FEV1 at 24 h (ITT population; mean ± SEM) after different doses of nebulized glycopyrrolate. *P < 0.001 ancova. n = 37–39

Figure 5

Plasma glycopyrrolate concentrations after different doses. , 12.5 μg; , 50 μg; , 100 μg; , 200 μg; , 400 μg