Impact on beclometasone dipropionate pharmacokinetics when switching to a low global warming potential propellant in a pressurised metered-dose inhaler.

Abstract

Introduction: Use of high global warming potential propellants (e.g., HFA-134a) for pressurised metered-dose inhalers (pMDIs) is being phased down. Beclometasone dipropionate (BDP) is approved for the treatment of asthma in several countries via an HFA-134a propellant pMDI. This is being reformulated using the low global warming potential propellant HFA-152a. Two studies compared BDP pharmacokinetics delivered via pMDI using HFA-152a vs HFA-134a.

Methods: Both studies (N=71/study) were single-dose (four inhalations of BDP), randomised, double-blind, crossover (Study 1, four-way; Study 2, two-way), in healthy volunteers. In Study 1, subjects inhaled BDP via HFA-134a pMDI in two periods (200 μg/actuation in one period, 100 μg/actuation in the other) and HFA-152a pMDI in the other two (200 or 100 μg/actuation). In Study 2, subjects inhaled BDP 200 μg/actuation via HFA-134a or HFA-152a pMDI using a spacer device. pMDIs containing HFA-152a and HFA-134a were compared in terms of lung availability (BDP comparisons) and total systemic exposure (beclometasone-17-monopropionate comparisons [B17MP; active metabolite of BDP]), with bioequivalence concluded if the 90% confidence intervals (CIs) of the geometric mean ratios of maximum plasma concentration (C_max) and area under the plasma concentration-time curve between time zero and the last quantifiable timepoint (AUC_0-t) were between 80-125%.

Results: BDP C_max and AUC_0-t were equivalent for the two BDP 200 μg formulations, without (Study 1) and with spacer (Study 2). BDP 100 μg AUC_0-t met the bioequivalence criteria, but the C_max lower 90% CI was marginally below the bioequivalence limit (79.46%). B17MP C_max and AUC_0-t were bioequivalent with both propellants in all three comparisons.

Conclusions: Overall, bioequivalence was confirmed of HFA-152a and HFA-134a for BDP 200 μg/actuation, with and without a spacer. Although bioequivalence of the two formulations cannot be formally concluded for BDP 100 μg, the minimal difference suggests the two formulations can be considered therapeutically equivalent.