A scintigraphy study of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler in patients with moderate-to-very severe chronic obstructive pulmonary disease

Abstract

Background: Triple therapy with inhaled corticosteroids/long-acting muscarinic antagonists/long-acting β₂-agonists (ICS/LAMA/LABA) is recommended for patients with chronic obstructive pulmonary disease (COPD) with continued symptoms or exacerbations, despite treatment with LAMA/LABA or ICS/LABA. The pulmonary, extrathoracic, and regional lung deposition patterns of a radiolabeled ICS/LAMA/LABA triple fixed-dose combination budesonide/glycopyrrolate/formoterol fumarate (BGF 320/18/9.6 μg), delivered via a single Aerosphere metered dose inhaler (MDI) were previously assessed in healthy volunteers and showed good deposition to the central and peripheral airways (whole lung deposition: 37.7%). Here, we report the findings assessing BGF in patients with moderate-to-very severe COPD.

Methods: This phase I, single-dose, open-label gamma scintigraphy imaging study (NCT03906045) was conducted in patients with moderate-to-very severe COPD. Patients received two actuations of BGF MDI (160/9/4.8 μg per actuation) radiolabeled with technetium‑99‑pertechnetate, not exceeding 5 MBq per actuation. Immediately following each inhalation, patients performed a breath-hold of up to 10 s, then exhaled into an exhalation filter. Gamma scintigraphy imaging of the anterior and posterior views of the lungs and stomach, and a lateral head and neck view, were performed immediately after exhalation. The primary objective of the study was to assess the pulmonary deposition of BGF. Secondary objectives assessed the deposited dose of radiolabeled BGF in the oropharyngeal and stomach regions, on the actuator, and on the exhalation filter in addition to regional airway deposition patterns in the lungs.

Results: The mean BGF emitted dose deposited in the lungs was 32.1% (standard deviation [SD] 15.6) in patients with moderate-to-very severe COPD, 35.2% (SD 12.8) in patients with moderate COPD, and 28.7% (SD 18.4) in patients with severe/very severe COPD. Overall, the mean normalized outer/inner ratio was 0.55 (SD 0.19), while the standardized central/peripheral ratio was 2.21 (SD 1.64).

Conclusions: Radiolabeled BGF 320/18/9.6 μg was efficiently delivered and deposited throughout the entire lung, including large and small airways, in patients with moderate-to-very severe COPD, with similar deposition in patients with moderate COPD and patients with severe/very severe COPD.

Trial registration: ClinicalTrials.gov, NCT03906045. Registered 8 April 2019, https://clinicaltrials.gov/ct2/show/NCT03906045.

Keywords: Budesonide; Formoterol fumarate; Gamma scintigraphy; Glycopyrronium; Pulmonary deposition.

Fig. 1

Study design. ⁵⁷Co cobalt-57, ^81mKr Krypton-81 m, BGF budesonide/glycopyrrolate/formoterol fumarate, COPD chronic obstructive pulmonary disease, MDI metered dose inhaler

Fig. 2

Aerodynamic particle size distribution from BGF MDIs. Comparison of budesonide, glycopyrrolate, and formoterol fumarate aerodynamic particle size distribution from non-radiolabeled BGF MDIs and radiolabeled BGF MDIs used in this study. The effective cut-off particle size for each stage is shown for an inhalation flow rate of 30 L/min. BD budesonide, BGF budesonide/glycopyrrolate/formoterol fumarate, FF formoterol fumarate, GP glycopyrrolate, MOC micro-orifice collector, MDI metered dose inhaler, NGI Next Generation Impactor

Fig. 3

Patient disposition. ^aOne patient was excluded due to improper MDI inhalation technique. BGF budesonide/glycopyrrolate/formoterol fumarate, COPD chronic obstructive pulmonary disease, MDI metered dose inhaler, PP per protocol

Fig. 4

Representative gamma scintigraphy posterior view images of ^81mKr gas ventilation (left) and lung deposition of BGF (right) in a patient with a moderate COPD and a patient with b severe/very severe COPD (PP analysis set). ^81mKr Krypton-81 m, BGF budesonide/glycopyrrolate/formoterol fumarate, COPD chronic obstructive pulmonary disease, PP per protocol

Fig. 5

Derived deposition data for percentage emitted dose and regional deposition ratios in the lung by COPD severity (PP analysis set). ∆ LSM difference for severe/very severe vs. moderate COPD (95% CI), CI confidence interval, COPD chronic obstructive pulmonary disease, C/P central to peripheral, LSM least squares mean, O/I outer to inner, PI penetration index, PP per protocol, sC/P standardized central/peripheral, SE standard error