Dose proportionality of fluticasone propionate from hydrofluoroalkane pressurized metered dose inhalers (pMDIs) and comparability with chlorofluorocarbon pMDIs

Fluticasone propionate pressurized metered dose inhalers (pMDIs) containing the hydrofluoroalkane (HFA) propellant, HFA 134a, are being developed to r eplace existing chlorofluorocarbon (CFC) pMDIs. This is part of the ongoing worlduride project to limit the damage to the earth's ozone layer. The in vivo performance and dose proportionality of fluticasone propionate HFA 134a pMDIs was examined for fluticasone propionate doses of 400, 1600 a nd 2000 mu g using the 50, 125 and 250 mu g strength pMDIs, respectively. T he 125 and 250 mu g strength HFA 134a pMDIs were compared with correspondin g fluticasone propionate CFC pMDIs. Twenty-three healthy subjects participa ted in this single dose, randomized, five-way, cross-over study. Serial blo od samples were collected 24 h post-dose to measure fluticasone propionate plasma concentrations. Twenty-four hour urinary-free cortisol was also meas ured before and after dosing. A dose-proportional increase in plasma fluticasone propionate concentration s was observed with increasing dose for the HFA 134a pMDIs. This was associ ated with a dose-related decrease in urinary cortisol excretion. Similar or lower fluticasone propionate systemic exposure was observed with the HFA 1 34a pMDIs compared to the corresponding CFC inhalers. The differences in sy stemic exposure observed for the HFA 134a and CFC pMDIs were too small to p roduce a differential effect on urinary cortisol excretion. Since fluticasone propionate has negligible oral bioavailability, the syste mic exposure, which arises only from pulmonary absorption, is a measure of lung deposition. There was a good correlation between the in vitro fine par ticle mass produced by the different strengths and types of pMDI and the sy stemic exposure to fluticasone propionate. Therefore, the fluticasone propi onate HFA 134a pMDI is an acceptable pharmaceutical alternative to the curr ent CFC pMDI, producing similar lung deposition and no increase in systemic exposure at microgram equivalent doses.