Fluticasone Furoate, a Novel Inhaled Corticosteroid, Demonstrates Prolonged Lung Absorption Kinetics in Man Compared with Inhaled Fluticasone Propionate

Fluticasone furoate (FF; GW685698) is a novel inhaled corticosteroid that is active at 24 h and under development for once-daily administration in combination with the long-acting β₂-adrenoceptor agonist vilanterol (GW642444) for chronic obstructive pulmonary disease and asthma. In vitro studies examining the respiratory tissue-binding properties of corticosteroids showed FF to have the largest cellular accumulation and slowest rate of efflux compared with other clinically used inhaled corticosteroids, consistent with greater tissue retention. The enhanced affinity of the glucocorticoid receptor binding of FF, coupled with its extended tissue association, may be expected to lead to greater and more prolonged anti-inflammatory effects and should provide relevant once-daily efficacy.

The aim of this study was to assess the rate and extent of systemic absorption of FF from the lung following inhaled administration of FF from three exploratory dry powder formulations (via DISKHALER^®) compared with inhaled fluticasone propionate (FP) [via DISKHALER^®] using deconvolution analysis.

This open-label, part-randomized, six-way crossover study evaluated three early development dry powder inhaled formulations of FF administered as single doses via DISKHALER^®. Healthy male subjects (n = 24) each received FF (2,000 μg; three formulations), inhaled FP (1,000 μg; via DISKHALER^®) and 250 μg of each molecule by intravenous infusion. The bioavailability of both inhaled FF and FP represents absorption from the lung as the oral bioavailability from the swallowed portion of the inhaled dose is negligible (<1.5 %). To investigate the absorption kinetics from the lung, the inhaled concentration–time data were subjected to deconvolution analysis using derived pharmacokinetic parameters from fitting of the intravenous concentration–time data.

The terminal elimination half-life (t_½β) for inhaled FF was considerably longer (range 17–24 h) than the t_½β estimated for intravenous FF (14 h), whereas t_½β for FP was similar whether inhaled or given intravenously (11 and 14 h, respectively). This would suggest that FF is exhibiting absorption rate-limited pharmacokinetics following inhaled FF dosing and that the apparent t_½β is an estimate of absorption rate. The lung mean absorption time for FF was approximately 7 h irrespective of formulation, which was considerably longer than FP (2.1 h). The time for 90 % absorption from the lung was significantly longer for FF (20–30 h) than for FP (8 h), indicating a significantly longer lung retention time for FF.

In comparison with inhaled FP, inhaled FF (independent of formulation) demonstrated prolonged absorption from the lung into the systemic circulation, indicating a longer lung retention time and suggesting the potential for maintained efficacy with once-daily administration.