Multiple-Dose Proportionality Study of Flunisolide Hydrofluoroalkane

The hydrofluoroalkane (HFA) formulation of the inhaled corticosteroid flunisolide is a modification of the original chlorofluorocarbon formulation. HFA flunisolide substitutes an HFA for a chlorofluorocarbon propellant and uses a built-in spacer in its pressurized metered-dose inhaler. An open-label, randomized, three-way crossover, multiple-dose study evaluated the dose proportionality of three doses of flunisolide HFA. Twenty-one healthy volunteers received the following doses twice daily for 4.5 days: 85, 170, and 340 g. Plasma levels of flunisolide and of the flunisolide metabolite 6-OH flunisolide were measured after single- and multiple-dose administration. After a single dose, dose proportionality was observed across the three dose levels for peak plasma concentration (C_max) and the area under the plasma concentration-time curve (AUC) up to both the time corresponding to the last measurable concentration (AUC_0-) and the time to infinity (AUC_0-∞). After multiple doses, dose proportionality was observed for both C_max and AUC at the medium and high doses. Predose plasma levels of flunisolide measured on day 4 were below the limit of detection. The elimination half-life of flunisolide ranged from 0.95 to 1.34 hours. After both single and multiple doses, dose proportionality was observed in dose-adjusted C_max and AUC_0-∞ for the inactive 6-OH metabolite. HFA flunisolide was well tolerated. The lack of accumulation after repeated administration of HFA flunisolide suggests that the systemic exposure of flunisolide is low, which is a safety goal for inhaled corticosteroids.