Bioequivalence of budesonide/glycopyrrolate/formoterol fumarate with a next-generation propellant versus hydrofluoroalkane-134a in healthy adults: phase I, randomized, double-blind, single-dose, partial-replicate, three-way cross-over lung exposure and total systemic exposure studies

Background: Hydrofluoroolefin-1234ze (HFO-1234ze) is a next-generation propellant with 99.9% lower global warming potential (GWP) than hydrofluoroalkane-134a (HFA-134a). Objectives: We report systemic and lung exposure bioequivalence for budesonide/glycopyrrolate/formoterol fumarate (BGF) components with HFO-1234ze versus HFA-134a. Design: These phase I, randomized, double-blind, single-dose, 3-way cross-over trials in healthy adults included three phases (screening; three single-dose treatment periods with 3- to 7-day washouts; follow-up). Methods: Participants were randomized to four BGF inhalations (160/9/4.8 µg/actuation) with test (HFO-1234ze) or reference (HFA-134a) treatments in one of three sequences, with HFA-134a administered during two of the three treatment periods. For lung exposure, oral activated charcoal was administered before and after treatment. Bioequivalence was considered established if the 90% confidence interval (CI) for the geometric mean ratio (GMR) was within 80%–125% (or expanded limits, if appropriate) for maximum plasma concentration (Cmax), area under the plasma concentration–curve from time zero to the last quantifiable concentration (AUClast) and AUC from time zero to infinity (AUCinf; US approach only). Results: Bioequivalence criteria were met across BGF components. The 90% CI for the GMR was within 80%–125% (or expanded limits) for HFO-1234ze versus HFA-134a, for systemic (GMR: Cmax, 85.41–99.29; AUClast, 95.74–102.48; AUCinf, 90.72–102.58) and lung (GMR: Cmax, 93.39–104.24, AUClast, 97.02–107.76; AUCinf, 101.45–112.22) exposure. No serious adverse events were reported. Conclusion: Total systemic and lung exposure to all BGF components met bioequivalence criteria for HFO-1234ze versus HFA-134a, with no new or unexpected safety findings. The near-zero GWP HFO-1234ze propellant is a viable replacement for HFA-134a. Trial registration: NCT05569421 (clinicaltrials.gov/study/NCT05569421) and NCT05477108 (clinicaltrials.gov/study/NCT05477108).