Flunisolide HFA vs flunisolide CFC: pharmacokinetic comparison in healthy volunteers.

Abstract

Two preparations of flunisolide, an inhaled corticosteroid, were compared in a parallel, multiple-dose study of 31 healthy volunteers. The new flunisolide preparation substitutes hydrofluoroalkane (HFA) for chlorofluorocarbon (CFC) as a propellant and incorporates a spacer into its pressurized metered-dose inhaler (pMDI). In this study, subjects were randomly assigned to receive flunisolide CFC 1000 microg bid; flunisolide HFA 170 microg bid; or flunisolide HFA 340 microg bid. Dosing was continued for 13.5 days. Plasma samples were analyzed after the first dose on day 1 and again after 13.5 days of treatment. No significant differences in day 1 dose-adjusted peak plasma concentrations (C(max)) were observed. Dose proportionality in C(max) and area under the concentration--time curves (AUC) was observed for the flunisolide HFA 170 and 340 microg bid groups on days 1 and 14. Day 1 mean dose-adjusted AUC was significantly greater in the flunisolide CFC 1000 microg bid group than in either flunisolide HFA group, indicating greater systemic availability of flunisolide CFC. Oral clearance and volume of distribution were significantly higher for flunisolide CFC than for flunisolide HFA. This may be due to greater oropharyngeal deposition by the flunisolide CFC formulation. Another indicator of greater flunisolide CFC oropharyngeal deposition was observed in C(max) and AUC(0--tlast) values for 6beta-OH flunisolide, the first-pass metabolite of flunisolide. The values of these pharmacokinetic parameters were significantly higher in the flunisolide CFC group than in the 340 microg bid flunisolide HFA group on days 1 and 14. However, this was not the case for cortisol values where flunisolide HFA accounted for less oropharyngeal deposition and more targeted delivery without adverse events. The study demonstrated that flunisolide HFA administered through a pMDI with built-in spacer was safe and well tolerated in healthy volunteers.