Evaluating the pharmacokinetics of beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide delivered via pressurised metered-dose inhaler using a low global warming potential propellant

François Rony; Mauro Cortellini; Alessandro Guasconi; Kusum S Mathews; Annalisa Piccinno; Gianluigi Poli; Frédéric Vanhoutte; Jelle Klein

doi:10.1016/j.pupt.2024.102299

Evaluating the pharmacokinetics of beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide delivered via pressurised metered-dose inhaler using a low global warming potential propellant

Pulm Pharmacol Ther. 2024 Apr 23:85:102299. doi: 10.1016/j.pupt.2024.102299. Online ahead of print.

Authors

François Rony¹, Mauro Cortellini², Alessandro Guasconi², Kusum S Mathews², Annalisa Piccinno², Gianluigi Poli², Frédéric Vanhoutte³, Jelle Klein³

Affiliations

¹ Global Clinical Development, Chiesi SAS, Bois Colombes, France. Electronic address: f.rony@chiesi.com.
² Global Clinical Development, Chiesi Farmaceutici SpA, Parma, Italy.
³ Clinical Pharmacology Unit, SGS Belgium NV, Edegem, Belgium.

PMID: 38663512
DOI: 10.1016/j.pupt.2024.102299

Abstract

Introduction: Use of propellants with high global warming potential (such as HFA-134a) for pressurised metered-dose inhalers (pMDIs) is being phased down. Switching to dry-powder inhalers may not be clinically feasible for all patients; an alternative is reformulation using propellants with low global warming potential. The combination of beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB) is available for asthma or chronic obstructive pulmonary disease via pMDI using HFA-134a as propellant. This is being reformulated using the low global warming potential propellant HFA-152a. This manuscript reports three studies comparing BDP/FF/GB pharmacokinetics delivered via pMDI using HFA-152a vs HFA-134a.

Methods: The studies were four-way crossover, single-dose, randomised, double-blind, in healthy volunteers. In Studies 1 and 2, subjects inhaled four puffs of BDP/FF/GB (Study 1: 100/6/12.5 μg [medium-strength BDP]; Study 2: 200/6/12.5 μg [high-strength]), ingesting activated charcoal in two of the periods (once per propellant). In Study 3, subjects inhaled medium- and high-strength BDP/FF/GB using a spacer. All three studies compared HFA-152a vs HFA-134a in terms of lung availability and total systemic exposure of beclometasone-17-monopropionate (B17MP; active metabolite of BDP), BDP, formoterol and GB. Bioequivalence was concluded if the 90 % confidence intervals (CIs) of the ratios between formulations of the geometric mean maximum plasma concentration (C_max) and area under the plasma concentration-time curve between time zero and the last quantifiable timepoint (AUC_0-t) for the analytes were between 80 and 125 %.

Results: In Studies 1 and 2, systemic exposure bioequivalence (i.e., comparisons without charcoal block) was demonstrated, except for GB C_max in Study 2 (upper 90 % CI 125.11 %). For lung availability (i.e., comparisons with charcoal block), B17MP and formoterol demonstrated bioequivalence in both studies, as did BDP in Study 2; in Study 1, BDP upper CIs were 126.96 % for C_max and 127.34 % for AUC_0-t). In Study 1, GB AUC_0-t lower CI was 74.54 %; in Study 2 upper limits were 135.64 % for C_max and 129.12 % for AUC_0-t. In Study 3, the bioequivalence criteria were met for BDP, B17MP and formoterol with both BDP/FF/GB strengths, and were met for GB AUC_0-t, although not for C_max. Both formulations were similarly well tolerated in all three studies.

Conclusions: Overall, while formal bioequivalence cannot be concluded for all analytes, these data suggest therapeutic equivalence of the new formulation with the existing BDP/FF/GB pMDI formulation, therefore supporting reformulation using a propellant with low global warming potential.

Keywords: Adrenergic beta-2 receptor agonists; Inhaled corticosteroids; Inhaled triple therapy; Lung bioavailability; Muscarinic antagonists; Total systemic exposure.