Pharmacokinetic and pharmacodynamic evaluation of fluticasone propionate after inhaled administration.
OBJECTIVE
To evaluate the pharmacokinetic and systemic pharmacodynamic properties of inhaled fluticasone propionate (FP).


METHODS
Single doses of 0.25, 0.5, 1.0 and 3.0 mg FP were administered to groups of six healthy subjects. Serum concentration profiles of FP were monitored over 24 h by means of high-performance liquid chromatography/mass spectrometry (HPLC/MS-MS). Systemic pharmacodynamic effects were evaluated by measuring endogenous serum cortisol and circulating white blood cells, and analyzed with previously developed integrated pharmacokinetic/pharmacodynamic (PK/PD) models.


RESULTS
FP showed a dose-independent terminal half-life with a mean (SD) of 6.0 (0.7) h. Maximum serum concentrations occurred 1.0 (0.5) h after administration, ranging from 90 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 and a known oral bioavailability of less than 1%, indicates prolonged residence at and slow absorption from the lungs. In the investigated dose range, the cumulative systemic effect was dose-dependent for both markers 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 159, 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, granulocytes and endogenous cortisol could be sufficiently characterized with the applied PK/PD models. The measured in vivo EC50 values, 30 pg.ml(-1) and 7.3 pg.ml(-1) for white blood cells and cortisol, respectively, were in good agreement with predictions based on the in vitro relative receptor affinity of FP.


CONCLUSIONS
After inhalation, FP follows linear pharmacokinetics and exhibits dose-dependent systemic pharmacodynamic effects that can be described by PK/PD modeling.
Möllmann
H
H
Medical Clinic Bergmannsheil, University of Bochum, Germany.
Wagner
M
M
Meibohm
B
B
Hochhaus
G
G
Barth
J
J
Stöckmann
R
R
Krieg
M
M
Weisser
H
H
Falcoz
C
C
Derendorf
H
H
D000280:Administration, Inhalation; D000328:Adult; D000730:Androstadienes / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D005260:Female; D000068298:Fluticasone; D006801:Humans; D008297:Male; D012016:Reference Values
D000730:Androstadienes; D018927:Anti-Asthmatic Agents; D000068298:Fluticasone