title: Multiple-dose proportionality study of flunisolide hydrofluoroalkane.
abstract: 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 micrograms. Plasma levels of flunisolide and of the flunisolide metabolite 6 beta-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 (Cmax) and the area under the plasma concentration-time curve (AUC) up to both the time corresponding to the last measurable concentration (AUC0-tau) and the time to infinity (AUC0-infinity). After multiple doses, dose proportionality was observed for both Cmax 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 Cmax and AUC0-infinity for the inactive 6 beta-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.
authors.affiliation: Department of Pharmacokinetics, Forest Laboratories, Inc., Harborside Financial Center, Plaza Three, Suite 602, Jersey City, NJ 07311, USA.
authors.forename: Arno
authors.initials: A
authors.lastname: Nolting
authors.forename: Wattanaporn
authors.initials: W
authors.lastname: Abramowitz
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D018927:Anti-Asthmatic Agents / Q000097:blood* / Q000494:pharmacology* / Q000627:therapeutic use; D019540:Area Under Curve; D001249:Asthma / Q000188:drug therapy*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005446:Fluocinolone Acetonide / Q000031:analogs & derivatives* / Q000097:blood* / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000097:blood* / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D012016:Reference Values; D013997:Time Factors
chemical_list: D018927:Anti-Asthmatic Agents; D006845:Hydrocarbons, Fluorinated; D005446:Fluocinolone Acetonide; C007734:flunisolide