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.

Artur Bednarczyk, Magnus Aurivillius, Mandeep Jassal, Mihir Shah, Ibrahim Raphiou, David Petullo, John Xu, Maria Heijer, Klementyna Sychowicz, Kathryn Collison, Carlos Silva, Jitendar Reddy, David Han, Ronald Goldwater, Michael Gillen, Mehul Patel

Journal: Therapeutic advances in respiratory disease 2026;20():17534666261417149

PMID: 41677208

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Abstract

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).

Address: Respiratory and Immunology, Clinical Development, Biopharmaceuticals R&D, AstraZeneca Pharma Poland, Warsaw, Poland.; Respiratory and Immunology, Global Patient Safety, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.; Respiratory and Immunology, Clinical Development, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.; Respiratory and Immunology, Clinical Development, Biopharmaceuticals R&D, AstraZeneca, Durham, NC, USA.; Respiratory and Immunology, Biometrics, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.; Integrated Bioanalysis, Clinical Pharmacology and Safety Sciences, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.; Respiratory and Immunology, Clinical Operations, Biopharmaceuticals R&D, AstraZeneca, Durham, NC, USA.; Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, Biopharmaceuticals R&D, AstraZeneca, Cambridge, UK.; Parexel, Glendale, CA, USA.; Parexel, Baltimore, MD, USA.; Creek Lane PK, LLC, Waterford, VA, USA.; Respiratory & Immunology, Clinical Development, Biopharmaceuticals R&D, AstraZeneca, Academy House, 136 Hills Road, Cambridge CB2 8PA, UK.

DOI: 10.1177/17534666261417149

MeSH Terms: Humans, Therapeutic Equivalency, Cross-Over Studies, Double-Blind Method, Male, Adult, Female, Lung, Glycopyrrolate, Administration, Inhalation, Young Adult, Middle Aged, Aerosol Propellants, Hydrocarbons, Fluorinated, Bronchodilator Agents, Drug Combinations, Formoterol Fumarate, Budesonide, Formoterol Fumarate Drug Combination, Healthy Volunteers, Fluorocarbons