Lung Deposition of Inhaled Extrafine Beclomethasone Dipropionate/Formoterol Fumarate/Glycopyrronium Bromide in Healthy Volunteers and Asthma: The STORM Study

Abstract

Background: An extrafine formulation triple therapy combination of beclomethasone dipropionate (BDP), formoterol fumarate (FF), and glycopyrronium bromide (GB) has been developed for the maintenance treatment of asthma and chronic obstructive pulmonary disease. This study used gamma scintigraphy to evaluate the intrapulmonary and extrapulmonary in vivo deposition of BDP/FF/GB, and the intrapulmonary regional distribution of the deposited formulation. Methods: This open-label uncontrolled nonrandomized single-dose study recruited 10 healthy volunteers and 9 patients with asthma. After a krypton-81m (81mKr) ventilation scan was conducted, subjects inhaled study drug (four inhalations of BDP/FF/GB 100/6/12.5 μg radiolabeled using technetium-99 m [99mTc]) through pressurized metered-dose inhaler, and a series of scintigraphic images were taken. The primary objective was to evaluate intrapulmonary drug deposition of BDP/FF/GB, determined as the percentage of nominal (i.e., metered) dose. Secondary endpoints included central/peripheral deposition ratio (C/P), and the standardized central/peripheral ratio (sC/P; 99mTc aerosol C/P/81mKr gas C/P). Results: All participants completed the study, with all scintigraphy procedures performed at one site. In patients with asthma, mean ± standard deviation intrapulmonary deposition was 25.50% ± 6.81%, not significantly different to that in healthy volunteers (22.74% ± 9.19%; p = 0.4715). Approximately half of the lung dose was deposited in the peripheral region of the lung (fraction deposited 0.52 ± 0.07 and 0.49 ± 0.06 in healthy volunteers and patients with asthma, respectively), resulting in C/P ratios of 0.94 ± 0.25 and 1.06 ± 0.25, respectively, with sC/P ratios of 1.80 ± 0.40 and 1.94 ± 0.38. Deposition patterns were similar in the two populations. BDP/FF/GB was well tolerated. Conclusions: This study confirmed that the extrafine particles delivered by BDP/FF/GB penetrate the peripheral areas of the lungs, with a similar proportion of particles deposited in the central and peripheral regions. Importantly, the deposition patterns were similar in healthy volunteers and patients with asthma, suggesting that disease characteristics are unlikely to impact drug deposition. Clinical Trial Registration number: NCT03795350.

Keywords: lung deposition; peripheral airways; radiolabeling; scintigraphy; triple therapy.

Conflict of interest statement

O.S.U. reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, and GlaxoSmithKline, personal fees from Cipla, Covis, Deva, Kamada, Kyorin, Menarini, Mereo Biopharma, Mundipharma, Napp, Novartis, Orion, Sandoz, Takeda, Trudell Medical, and UCB, and grants from Edmond Pharma, all of which are outside the submitted study. S.B., I.P., F.R., and G.G. are employees of Chiesi, the sponsor of the trial, and L.G. was engaged as a consultant by Chiesi. G.T. and S.W. are employees of Cardiff Scintigraphics Limited. W.D.B. has no relevant conflicts of interest to disclose.

Figures

FIG. 1.

Example scans (reflected posterior views) from a healthy volunteer (A is lung deposition and B shows ventilation) and a patient with asthma (with C showing lung deposition and D showing ventilation). The white line is the ventilated lung margin derived from the krypton-81m gas ventilation image (autocontour drawn by the nuclear medicine software that detects the margins of the lungs as those pixels with ∼10% of the maximum pixel count). The blue dotted line indicates the peripheral lung ROI, and the orange dotted line indicates the central lung ROI. The central and peripheral ROIs used here correspond to the inner and outer ROIs described in Newman et al.(10) ROI, region of interest.