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).