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

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    • Source:
      Publisher: Academic Press Country of Publication: England NLM ID: 9715279 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-9629 (Electronic) Linking ISSN: 10945539 NLM ISO Abbreviation: Pulm Pharmacol Ther Subsets: MEDLINE
    • Publication Information:
      Publication: London : Academic Press
      Original Publication: London ; New York : Academic Press, c1997-
    • Subject Terms:
    • 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.
      Competing Interests: Declaration of competing interest FR, MC, AG, KM, AP and GP are employees of Chiesi, the sponsor of the studies. FV and JK are employees of SGS, the clinical trial site. Both have no conflicts of interest to report.
      (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
    • Contributed Indexing:
      Keywords: Adrenergic beta-2 receptor agonists; Inhaled corticosteroids; Inhaled triple therapy; Lung bioavailability; Muscarinic antagonists; Total systemic exposure
    • Accession Number:
      KGZ1SLC28Z (Beclomethasone)
      W34SHF8J2K (Formoterol Fumarate)
      V92SO9WP2I (Glycopyrrolate)
      0 (Drug Combinations)
      0 (Aerosol Propellants)
      R40P36GDK6 (apaflurane)
      0 (Bronchodilator Agents)
      0 (Anti-Asthmatic Agents)
      0 (Fluorocarbons)
    • Publication Date:
      Date Created: 20240425 Date Completed: 20240610 Latest Revision: 20240829
    • Publication Date:
      20240830
    • Accession Number:
      10.1016/j.pupt.2024.102299
    • Accession Number:
      38663512