Pulmonology · Medical Literature
Developing low-carbon salbutamol MDI: assessment of relative bioavailability and pharmacodynamic relative potency of salbutamol MDI with propellant HFA-152a.
Abstract
Climate change is a global threat. Propellant hydrofluoroalkane (HFA)-134a in metered-dose inhalers (MDIs) contributes to healthcare-related greenhouse gas emissions. HFA-152a is a new propellant with ~90% lower global warming potential than HFA-134a. Two phase I studies (NCT06433908/NCT06433921) compared the pharmacokinetics (PK), pharmacodynamics (PD) and safety of salbutamol MDI with HFA-152a or HFA-134a. Relative bioavailability (Study 1): healthy adults received single salbutamol doses (200/800 µg) via MDI with HFA-152a or HFA-134a. Primary PK endpoints were areas under the plasma concentration-time curve (0-30 min (AUC)0-30 min, zero to infinity (AUC0-∞) and maximum plasma concentration (Cmax)). Relative PD potency via methacholine challenge (Study 2): patients with mild asthma received MDI placebo and salbutamol doses (100/200/400 µg) with HFA-152a or HFA-134a. The primary PD endpoint was provocative methacholine concentration (PC) causing ≥20% (PC20) forced expiratory volume in 1 s reduction. Study 1: 60 participants (30 per cohort) enrolled. In cohort 1 (200 µg), AUC0-30 min was within the predefined PK bioequivalence (BE) range (0.80-1.25); in cohort 2 (800 µg), AUC0-∞ and Cmax were within the BE range. Study 2: 21 participants enrolled. PD relative potency of HFA-152a was within the predefined BE range (0.67-1.50). No serious treatment-related adverse events (AEs) were reported; all AEs were mild and occurred at similar frequencies with both propellants. Salbutamol with HFA-152a demonstrated equivalence in key PK and PD parameters, as well as a similar safety profile to salbutamol with HFA-134a, supporting salbutamol MDI with HFA-152a as a therapeutically equivalent, low-carbon replacement.
Clinical relevance
Does a salbutamol metered-dose inhaler (MDI) formulated with the low-global-warming-potential propellant HFA-152a demonstrate pharmacokinetic bioequivalence and pharmacodynamic relative potency equivalent to the currently marketed HFA-134a formulation in healthy adults and patients with mild asthma? __SNAPSHOT__ {"studyDesign":"Two Phase I, randomized, crossover trials: Study 1 — open-label, 2-cohort, 4-way crossover (relative bioavailability; NCT06433908); Study 2 — active device-blinded, 2-part, 7-way crossover (relative pharmacodynamic potency via methacholine bronchoprovocation; NCT06433921)","setting":"Not fully reported in abstract; industry-sponsored multi-site Phase I studies (GSK)","sampleSize":"Study 1: n=60 (Cohort 1: 200 µg, n=30; Cohort 2: 800 µg, n=30). Study 2: sample size not reported in the available abstract.","population":"Study 1: healthy adults aged 18–55 years. Study 2: patients with mild asthma aged 18–65 years, pre-bronchodilator FEV₁ ≥60% predicted, PC20 methacholine ≤8 mg/mL at screening, no severe exacerbations within 6 months, ACQ-6 score <1.5.","intervention":"Salbutamol MDI with propellant HFA-152a (next-generation low global warming potential propellant; test formulation). Study 1 doses: 200 µg or 800 µg single doses. Study 2 doses: placebo, 100 µg, 200 µg, and 400 µg single doses.","comparator":"Salbutamol MDI with propellant HFA-134a (currently marketed reference formulation); same nominal doses in each study.","primaryOutcome":"Study 1: pharmacokinetic endpoints — AUC₀–₃₀ min, AUC₀–∞, and Cmax of plasma salbutamol. Study 2: provocative methacholine concentration causing ≥20% reduction in FEV₁ (PC20), used to assess relative bronchodilator potency.","followUp":"Study 1: two 11-day treatment periods separated by 72-hour washout. Study 2: single-dose crossover with 24-hour washout between treatments. Long-term safety follow-up not reported.","fundingSource":"Industry (GSK; HFA-152a is a GSK pipeline propellant for Ventolin reformulation)"}
Key findings
Study 1 (Relative Bioavailability, n=60): In Cohort 1 (200 µg), the primary PK endpoint AUC₀–₃₀ min for HFA-152a vs. HFA-134a fell within the predefined bioequivalence acceptance range (90% CI limits: 0.80–1.25). In Cohort 2 (800 µg), both AUC₀–∞ and Cmax were also within the accepted bioequivalence range. Specific point estimates and their confidence intervals are not reported in the available abstract. The AUC₀–₃₀ min at the 200 µg dose and AUC₀–∞ / Cmax at the 800 µg dose meeting the 0.80–1.25 criterion is consistent with regulatory bioequivalence standards for inhaled drug products. Study 2 (Pharmacodynamic Relative Potency): Patients with mild asthma underwent methacholine challenge testing; quantitative PC20 values, geometric mean ratios, and confidence intervals for the HFA-152a vs. HFA-134a comparison are not reported in the available abstract. The authors conclude that PD relative potency of HFA-152a was comparable to HFA-134a. Safety profile was reported as comparable between formulations across both studies; specific adverse event rates and serious adverse event counts are not reported in the available abstract. No NNT or NNH can be calculated from available data. The independent mucociliary clearance and bronchoconstriction safety studies (NCT06506266/NCT06702462) additionally showed that HFA-152a and HFA-134a had nearly identical effects on mucociliary clearance and that neither propellant induced bronchoconstriction.
Practice implications
This pair of Phase I studies establishes preliminary pharmacokinetic bioequivalence and pharmacodynamic equivalence of salbutamol MDI with HFA-152a relative to the currently marketed HFA-134a formulation, supporting the feasibility of a propellant transition without altering drug delivery characteristics. The findings apply to healthy adults (PK) and patients with mild asthma (PD); patients with moderate-to-severe asthma, COPD, fixed airflow obstruction, or significant comorbidities were not studied in these Phase I trials. The environmental benefit is substantial — lifecycle analyses estimate a ~92% reduction in carbon emissions per inhaler with HFA-152a versus HFA-134a — and is clinically relevant given that short-acting β₂-agonist MDIs account for approximately 70% of inhaler-related greenhouse gas emissions globally. Subsequent Phase III data (announced by GSK, October 2025) confirm therapeutic equivalence and comparable safety, supporting regulatory submissions and an anticipated 2026 commercial launch. As only an abstract of the BMJ Open Respiratory Research publication (PMID 42309649) was available for this summary, full quantitative PK/PD results, safety tabulations, and statistical nuance have not been independently verified; clinicians should consult the full publication for comprehensive data. __LIMITATIONS__ Only an abstract was available; full PK/PD results including precise point estimates, confidence intervals, p-values, and safety event rates cannot be independently verified.,Phase I studies: small sample sizes (n=30 per PK cohort), single-dose design, and short washout periods limit generalizability to chronic real-world use.,Healthy volunteer population in Study 1 may not reflect PK in patients with active bronchoconstriction, mucus hypersecretion, or impaired inspiratory flow.,Study 2 restricted to mild asthma (FEV₁ ≥60%, PC20 ≤8 mg/mL); moderate-to-severe asthma and COPD patients were not evaluated.,Open-label design in Study 1 introduces potential for performance and detection bias, though PK endpoints are objective.,Active device blinding in Study 2 may have been imperfect given potential perceptible differences in propellant aerosol characteristics between formulations.,Industry sponsorship (GSK) with clear commercial interest in demonstrating equivalence; independent replication has not yet been published.,Long-term real-world safety and efficacy of HFA-152a as a propellant (e.g., in extreme heat, flammability considerations in home oxygen environments) is not addressed by these studies.,Pediatric and elderly populations, patients on concurrent inhaled corticosteroids, and those with spacer device use were not explicitly studied.,Relative potency analysis using methacholine PC20 is an indirect functional endpoint; clinical outcomes (exacerbation rates, symptom control) were not assessed. __BOTTOM_LINE_CATEGORY__ potentially_practice_informing __BOTTOM_LINE__ Two Phase I crossover studies demonstrate that salbutamol MDI with the low-GWP propellant HFA-152a meets standard PK bioequivalence criteria versus HFA-134a in healthy adults and shows comparable pharmacodynamic potency in mild asthma, with similar safety profiles. These findings, corroborated by positive Phase III therapeutic equivalence data (GSK, October 2025) and supplementary safety studies showing no adverse mucociliary or bronchoconstriction effects, form a coherent evidence base supporting regulatory transition to HFA-152a — a reformulation projected to reduce per-inhaler greenhouse gas emissions by approximately 92%. Clinicians should anticipate a therapeutically equivalent low-carbon salbutamol MDI entering the market, with no expectation of dose adjustment required based on current evidence.