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

Abstract

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 (FEV₁) of the 30 subjects who completed the study was 51 ± 15%, with a FEV₁/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 FEV₁ at 60 min post-dose, without administration of charcoal, were 0.180 L and 0.220 L for GLY/eFlow and GLY/DPI, respectively; FEV₁ 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.

Keywords: Bioavailability; COPD; Glycopyrronium bromide; Nebulizer.

Fig. 1

The eFlow® CS (Magnair®) nebulizer system

Fig. 2

GOLDEN 7 study schematic. Washout of more than 7 days required approval by the Sponsor. All doses were administered at the same time of day (± 1 h), 7 days apart. ^aSubjects had follow-up telephone contact on Day 36 (± 1 day) to assess safety. Subjects who discontinued prior to Visit 6 had follow-up telephone contact 5 to 7 days after their last study treatment. EOT, end of treatment

Fig. 3

Mean (±SD) glycopyrronium bromide plasma concentration values by treatment (PK population). Note: Pre-dose was 15 min prior to dosing; 0 was immediately at the end of the inhalation or IV infusion. Unusually high concentration values of 77,400 pg/mL, 1,520,000 pg/mL, and 1,250,000 pg/mL were excluded from the PK analysis and descriptive statistics for three subjects receiving IV infusion 50 μg. Note: Lower SD bars are missing where values are below zero; negative values cannot be displayed on a logarithmic scale. DPI, dry powder inhaler. GLY, glycopyrronium bromide. IV, intravenous. PK, pharmacokinetic. SD, standard deviation

Fig. 4

Comparison of GLY/eFlow versus GLY/DPI fully dose-normalized systemic exposure to glycopyrronium bromide. Note: Lower SD bars are missing where values are below zero; negative values cannot be displayed on a logarithmic scale. DPI, dry powder inhaler. GLY, glycopyrronium bromide. IV, intravenous. SD, standard deviation

Fig. 5

Summary of mean FEV₁ (L) by time point on treatment day. CI, confidence interval. DPI, dry powder inhaler. FEV₁, forced expiratory volume in 1 s. GLY, glycopyrronium bromide