PHARMACOKINETIC PHARMACODYNAMIC EVALUATION OF SYSTEMIC EFFECTS OF FLUNISOLIDE AFTER INHALATION/

The pharmacokinetics and pharmacodynamics of flunisolide were studied in healthy volunteers after inhalation. In the morning on the day the study began, volunteers inhaled 0.5 mg of flunisolide with and without oral administration of charcoal, or 1 mg, 2 mg, and 3 mg of flunisoli de with concomitant administration of charcoal. A placebo group was us ed to assess the endogenous cortisol, granulocyte, and lymphocyte base line levels. Flunisolide plasma levels were determined by high-perform ance liquid chromatography using a tandem mass spectrometer as detecto r (HPLC/MS/MS). Cortisol plasma levels and differential white blood ce ll counts were obtained over 12 hours. An integrated pharmacokinetic/p harmacodynamic (PK/PD) model was applied to link the flunisolide plasm a concentrations with the effects on lymphocytes, granulocytes, and co rtisol. Maximum concentration levels of 3 to 9 ng/mL of flunisolide we re observed after 0.2 to 0.3 hours for all of the investigated doses. The terminal half-life ranged from 1.3 to 1.7 hours. There was no stat istical difference between treatments in the presence or absence of or ally administered charcoal. The pharmacokinetic/pharmacodynamic (PK/PD ) models satisfactorily described the time-courses of the effects on g ranulocytes, lymphocytes, and cortisol suppression. The resulting E-50 -values (concentrations to induce 50% of the maximum effect) concurred with the reported values of in vitro receptor binding affinities. The duration of the systemic effects were short because of the short half -life of the drug. Cumulative cortisol suppression increased with dose administration and ranged from 20% to 36%. The PK/PD simulations resu lted in a smaller degree of cortisol suppression for the drug administ ered at 10 PM. The cumulative change from baseline was slightly smalle r for the effects on granulocytes and lymphocytes than those on cortis ol. This information promotes the comparison with other inhaled glucoc orticoids.