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European Journal of Clinical Pharmacology

, Volume 53, Issue 6, pp 459–467 | Cite as

Pharmacokinetic and pharmacodynamic evaluation of fluticasone propionate after inhaled administration

  • H. Möllmann
  • M. Wagner
  • B. Meibohm
  • G. Hochhaus
  • J. Barth
  • R. Stöckmann
  • M. Krieg
  • H. Weisser
  • C. Falcoz
  • H. Derendorf
PHARMACOKINETICS AND DISPOSITION

Abstract

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.

Conclusion: After inhalation, FP follows linear pharmacokinetics and exhibits dose-dependent systemic pharmacodynamic effects that can be described by PK/PD modeling.

Key words Fluticasone propionate Inhalation 

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Copyright information

© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • H. Möllmann
    • 1
  • M. Wagner
    • 1
  • B. Meibohm
    • 2
  • G. Hochhaus
    • 2
  • J. Barth
    • 1
  • R. Stöckmann
    • 1
  • M. Krieg
    • 1
  • H. Weisser
    • 1
  • C. Falcoz
    • 3
  • H. Derendorf
    • 2
  1. 1.Medical Clinic “Bergmannsheil”, University of Bochum, D-44789 Bochum, GermanyDE
  2. 2.100494 College of Pharmacy, University of Florida, Gainesville FL 32610, USA Tel.: +1 352 846-2726; Fax: +1 352 392-4447 e-mail: hartmut@cop.health.ufl.eduUS
  3. 3.Glaxo Wellcome Research and Development Ltd, Greenford, Middlesex, UKGB

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