PHARMACOKINETIC AND PHARMACODYNAMIC EVALUATION OF FLUTICASONE PROPIONATE AFTER INHALED ADMINISTRATION

Objective: To evaluate the pharmacokinetic and systemic pharmacodynami c properties of inhaled fluticasone propionate (FP). Methods: Single d oses of 0.25, 0.5, 1.0 and 3.0 mg FP were administered to groups of si x healthy subjects. Serum concentration pro files of FP were monitored over 24 h by means of high-performance liquid chromatography/mass spe ctrometry (HPLC/MS-MS). Systemic pharmacodynamic effects were evaluate d by measuring endogenous serum cortisol and circulating white blood c ells, and analyzed with previously developed integrated pharmacokineti c/pharmacodynamic (PK/PD) models. Results: FP showed a dose-independen t terminal half-life with a mean (SD) of 6.0 (0.7) h. Maximum serum co ncentrations occurred 1.0 (0.5) h after administration, ranging from 9 0 pg.ml(-1) for the 0.25 mg dose to 400 pg.ml(-1) for the 3.0 mg dose. This, together with an estimated mean absorption time of nearly 5 h a nd a known oral bioavailability of less than 1%, indicates prolonged r esidence at and slow absorption from the lungs. In the investigated do se range, the cumulative systemic effect was dose-dependent for both m arkers of pharmacodynamic activity. For doses of 0.25, 0.50, 1.0 and 3 .0 mg FP, the PK/PD-based cumulative systemic-effect parameters were 1 59, 186, 257 and 372%.h for lymphocyte suppression, 107, 186, 202 and 348%.h for granulocyte induction and 23.6%, 33.8%, 51.0% and 73.6% for cortisol reduction, respectively. The time courses of lymphocytes, gr anulocytes and endogenous cortisol could be sufficiently characterized with the applied PK/PD models. The measured in vivo EC50 values, 30 p g.ml(-1) and 7.3 pg.ml(-1) for white blood cells and cortisol, respect ively, were in good agreement with predictions based on the in vitro r elative receptor affinity of FP. Conclusion: After inhalation, FP foll ows linear pharmacokinetics and exhibits dose-dependent systemic pharm acodynamic effects that can be described by PK/PD modeling.