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
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".