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A Pharmacokinetic/Pharmacodynamic Approach to Predict the Cumulative Cortisol Suppression of Inhaled Corticosteroids
Authors:Bernd Meibohm  Günther Hochhaus  Helmut Möllmann  Jürgen Barth  Melanie Wagner  Michael Krieg  Ricarda Stöckmann  Hartmut Derendorf
Institution:(1) Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, 32610;(2) Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee, Memphis, Tennessee, 38163;(3) Medical Clinic lsquoBergmannsheil,rsquo, University of Bochum, 44789 Bochum, Germany;(4) Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, 32610
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 mgrg, FLU 500 mgrg, and TCA 1000 mgrg. For multiple dosing, a respective CCS of 28–33% was calculated for FLU 500 mgrg bid, FP 250 mgrg, bid, and TCA 1000 mgrg 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.
Keywords:PK/PD modeling  corticosteroids  cortisol suppression  surrogate marker  inhalation
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