Systemic Exposure of Budesonide/Glycopyrrolate/Formoterol Fumarate With Hydrofluoroolefin-1234ze Versus Hydrofluoroalkane-134a Propellants Administered Via Metered-Dose Inhaler With a Spacer in Healthy Adults

Abstract Rationale: Hydrofluoroolefin-1234ze (HFO-1234ze) propellant is in development for pressurized metered-dose inhalers (pMDIs), having >99.9% lower global warming potential (GWP) versus hydrofluoroalkane-134a (HFA-134a) propellant. Spacers are used with pMDIs to improve drug exposure. We assessed total systemic exposure of budesonide/glycopyrrolate/formoterol fumarate (BGF) pMDI components with a spacer for HFO-1234ze versus HFA-134a, and for HFO-1234ze with versus without a spacer. Methods: This Phase 1, randomized, partial double-blind, single-dose, single-center, 3-way crossover study (NCT06297668) included healthy participants aged 18-60 years with forced expiratory volume in 1 second (FEV1) ≥80% predicted normal value and a ratio of FEV1/forced vital capacity >70%. The study included a screening period, three treatment periods with 3- to 7-day between-period washouts, and a follow-up period. Randomized participants received BGF (4 inhalations of 160/9/4.8 µg as a single-dose) with reference (HFA-134a with spacer; treatment A) and test (HFO-1234ze with spacer; treatment B) formulations and HFO-1234ze without a spacer (open label; treatment C) in 1 of 6 treatment sequences (ABC, ACB, BAC, BCA, CAB, and CBA). The primary pharmacokinetic endpoints were maximum observed plasma concentration (Cmax) and area under the plasma concentration curve from time zero to the time of the last quantifiable concentration (AUClast) for each BGF component. If the upper 90% confidence interval (CI) of the geometric mean ratio (GMR) for treatment B versus A was <125% for both primary endpoints across components, exposure with HFO-1234ze was considered not to exceed that of HFA-134a. BGF components’ relative bioavailabilities with HFO-1234ze with versus without a spacer were assessed using similar methods. Safety and tolerability were also assessed. Results: 42 participants were randomized (mean age, 44.5 years; male, 57.1%). With a spacer, the upper 90% CI of the GMRs for Cmax and AUClast were <125% for each BGF component for HFO-1234ze versus HFA-134a (Table). Cmax was increased for all BGF components for HFO-1234ze with versus without a spacer, with no increase observed for AUClast. Adverse events (AEs) were reported in 7.3% (HFA-134a with spacer), 14.3% (HFO-1234ze with spacer), and 14.3% (HFO-1234ze without spacer) of participants. No serious AEs or deaths were reported. Conclusion: With a spacer, total systemic exposure to BGF components with HFO-1234ze propellant did not exceed that of HFA-134a propellant, with no new safety findings. With HFO-1234ze, all BGF components had improved bioavailability with versus without a spacer based on Cmax, while similar relative bioavailability was observed for AUClast. These data support use of HFO-1234ze in BGF pMDIs.