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A Pharmacokinetic/Pharmacodynamic Approach to Predict the Cumulative Cortisol Suppression of Inhaled Corticosteroids

  • Bernd Meibohm
  • Günther Hochhaus
  • Helmut Möllmann
  • Jürgen Barth
  • Melanie Wagner
  • Michael Krieg
  • Ricarda Stöckmann
  • Hartmut Derendorf
Article

Abstract

The suppression of endogenous cortisol release is one of the major systemic side effects of inhaled corticosteroids in the treatment of asthma. The circadian rhythm of the endogenous cortisol release and the resulting plasma concentrations as well as the release suppression during corticosteroid therapy could previously be described with an integrated PK/PD model. Based on this model, a PK/PD approach was developed to quantify and predict the cumulative cortisol suppression (CCS) as a surrogate marker for the systemic activity of inhaled corticosteroid therapy. The presented method was applied to predict CCS after single doses and during short-term multiple dosing of the inhaled corticosteroids flunisolide (FLU), fluticasone propionate (FP), and triamcinolone acetonide (TCA), and after oral methylprednisolone as systemic reference therapy. Drug-specific PK and PD parameters were obtained from previous single-dose studies and extrapolated to the multiple-dose situation. For single dosing, a similar CCS within the range of 16–21% was predicted for FP 250 μg, FLU 500 μg, and TCA 1000 μg. For multiple dosing, a respective CCS of 28–33% was calculated for FLU 500 μg bid, FP 250 μg, bid, and TCA 1000 μg bid. Higher cortisol suppression compared to these single and multiple dosing regimens of the inhaled corticosteroids was predicted after oral doses of only 1 mg and 2 mg methylprednisolone, respectively. The predictive power of the approach was evaluated by comparing the PK/PD-based simulations with data reported previously in clinical studies. The predicted CCS values were in good correlation with the clinically observed results. Hence, the presented PK/PD approach allows valid predictions of CCS for single and short-term multiple dosing of inhaled corticosteroids and facilitates comparisons between different dosing regimens and steroids.

PK/PD modeling corticosteroids cortisol suppression surrogate marker inhalation 

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Copyright information

© Plenum Publishing Corporation 1999

Authors and Affiliations

  • Bernd Meibohm
    • 1
    • 2
  • Günther Hochhaus
    • 1
  • Helmut Möllmann
    • 3
  • Jürgen Barth
    • 3
  • Melanie Wagner
    • 3
  • Michael Krieg
    • 3
  • Ricarda Stöckmann
    • 3
  • Hartmut Derendorf
    • 4
  1. 1.Department of PharmaceuticsCollege of Pharmacy, University of FloridaGainesvilleFlorida
  2. 2.Department of Pharmaceutical SciencesCollege of Pharmacy, University of TennesseeMemphis
  3. 3.Medical Clinic ‘Bergmannsheil,’University of BochumBochumGermany
  4. 4.Department of PharmaceuticsCollege of Pharmacy, University of FloridaGainesvilleFlorida

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