Evaluation of systemic absorption and bronchodilator effect of glycopyrronium bromide delivered by nebulizer or a dry powder inhaler in subjects with chronic obstructive pulmonary disease

BACKGROUND: Effective bronchodilator therapy depends upon adequate drug deposition in the lung. COPD patients who are unable to administer medications efficiently with conventional inhalers may benefit from the use of a nebulizer device. The aim of this study was to evaluate the systemic bioavailability and bronchodilator response of glycopyrronium bromide (GLY) administered by a novel nebulizer (eFlow® closed system [CS] vibrating membrane nebulizer) or dry powder inhaler (DPI) in subjects with moderate-to-severe chronic obstructive pulmonary disease (COPD). METHODS: In this randomized, open-label, single-dose, five-way crossover study, subjects received a sequence of either 50 μg GLY delivered by eFlow CS nebulizer (GLY/eFlow) or 63 μg GLY delivered by DPI (GLY/DPI), with and without activated charcoal, followed by intravenous infusion of 50 μg GLY with a washout period of 7 days between doses. Endpoints included plasma pharmacokinetics, safety and efficacy. RESULTS: The mean (± SD) baseline predicted forced expiratory volume in 1 s (FEV(1)) of the 30 subjects who completed the study was 51 ± 15%, with a FEV(1)/forced vital capacity ratio of 50 ± 11%. Without charcoal, the absolute systemic bioavailability of GLY/eFlow and GLY/DPI were approximately 15 and 22%, respectively. Changes from baseline in FEV(1) at 60 min post-dose, without administration of charcoal, were 0.180 L and 0.220 L for GLY/eFlow and GLY/DPI, respectively; FEV(1) improvements were similar when charcoal was administered (0.220 L for both GLY/eFlow and GLY/DPI). There were no significant differences in spirometry between the two devices. Fewer subjects administered GLY/eFlow reported adverse events (n = 15) than GLY/DPI (n = 18). CONCLUSIONS: After single doses, GLY/DPI delivered numerically higher peak and steady state levels of drug than did GLY/eFlow. Nebulized GLY produced similar bronchodilation but lower systemic levels of drug than GLY/DPI. Slightly higher number of subjects reported adverse events with GLY/DPI than with GLY/eFlow. Nebulized GLY may offer an effective alternative to patients with COPD not adequately treated with other devices. TRIAL REGISTRATION: NCT02512302 (ClinicalTrials.gov). Registered 28 May 2015. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12931-019-1113-z) contains supplementary material, which is available to authorized users.