Systemic Exposure and Implications for Lung Deposition with an Extra-Fine Hydrofluoroalkane Beclometasone Dipropionate/Formoterol Fixed Combination

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Abstract
Foster™ is a fixed combination of beclometasone dipropionate/formoterol (BDP/F). It is formulated as an extra-fine solution and delivered via a pressurized metered-dose inhaler (pMDI) using a hydrofluoroalkane (HFA) propellant. The aims of this study were to compare the systemic exposure to BDP, to its active metabolite beclometasone-17-monopropionate (B17MP) and to formoterol after administration of BDP/F versus separate administration of a chlorofluorocarbon (CFC) formulation of BDP and formoterol HFA, and to explore a possible relationship between pharmacokinetic and pharmacodynamic findings. In this open-label, crossover, placebo-controlled study, 12 healthy male subjects received a single dose of BDP/F 400 µg/24 µg (four inhalations of Foster™ BDP/F 100 µg/6 µg), single doses of BDP CFC 1000 µg (four inhalations of Becotide™ Forte 250 µg) plus formoterol 24 µg (four inhalations of Atimos® 6 µg) via separate MDIs, or placebo. Continuous pharmacokinetic variables for BDP, B17MP, formoterol, cortisol and potassium were evaluated. Cardiovascular effects, peak flow measurements and tolerability were also examined. Exposure to BDP was not significantly different between active treatment arms, but lower systemic exposure to B17MP was observed with the fixed combination than with the separate components (area under the plasma concentration-time curve [AUC] from time zero to infinity [AUC∞] 5280 vs 8120pg · h/mL; p = 0.001). Despite a lower total systemic exposure to B17MP with the fixed combination, B17MP plasma concentrations during the first 30 minutes after administration, indicative of pulmonary absorption, were 86% higher with BDP/F than with the separate components (AUC from 0 to 30 minutes [AUC30 min] 353 vs 190pg · h/mL; p = 0.003). Twenty-four-hour serum cortisol concentrations were significantly higher with BDP/F than with BDP and formoterol administered separately (2.26 vs 1.90 µg · h/mL; p < 0.01). No significant differences in the pharmacokinetic parameters of formoterol and no clinically relevant differences in serum potassium and cardiovascular or spirometric parameters were observed between the treatments. Both active treatments were well tolerated. These pharmacokinetic data show that with a BDP dose from Foster™ that is 2.5 times less than a BDP dose from Becotide™ Forte, pulmonary absorption is 86% higher; however, systemic exposure is 35% lower, resulting in less cortisol suppression for a similar BDP dosage.