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

AimsTo 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). MethodsPatients 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 (12.5-400g) and placebo via a high efficiency nebulizer (eFlow (R) PARI nebulizer), with washout between treatments. Plasma pharmacokinetics were assessed in a subset of patients (n = 11). ResultsAll 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 QT(c) interval. Following treatment with EP-101 at all doses there was a rapid bronchodilator response within 5min. Significant improvements in mean change from baseline FEV1 at 24h were reported at doses 50g compared with placebo, with a clear dose-response relationship. Mean changes in FEV1 were 0.10l (95% CI 0.06, 0.14) and 0.12l (95% CI 0.08, 0.16) for 100g and 200g, respectively. ConclusionSingle doses of EP-101 ranging from 12.5g to 400g 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 24h period at all doses >50g.