A pharmacokinetic/pharmacodynamic approach to predict the cumulative cortisol suppression of inhaled corticosteroids

The suppression of endogenous cortisol release is one of the major systemic side effects of inhaled corticosteroids in the treatment of asthma. The ci rcadian rhythm of the endogenous cortisol release and the resulting plasma concentrations as well as the release suppression during corticosteroid the rapy 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 cum ulative cortisol suppression (CCS) as a surrogate marker for the systemic a ctivity 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 s ystemic reference therapy. Drug-specific PK and PD parameters were obtained from previous single-dose studies and extrapolated to the multiple-dose si tuation. For single dosing, a similar CCS within the range of 16-21% was pr edicted for FP 250 mu g, FLU 500 mu g, and TCA 1000 mu g. For multiple dosi ng, a respective CCS of 28-33% was calculated for FLU 500 mu g bid, FP 250 mu g, bid, and TCA 1000 mu g bid. Higher cortisol suppression compared to t hese single and multiple dosing regimens of the inhaled corticosteroids was predicted after oral doses of only 1 mg and 2 mg methylprednisolone, respe ctively. The predictive power of the approach was evaluated by comparing th e PK/PD-based simulations with data reported previously in clinical studies . The predicted CCS values were in good correlation with the clinically obs erved results. Hence, the presented PK/PD approach allows valid predictions of CCS for single and short-term multiple dosing of inhaled corticosteroid s and facilitates comparisons between different dosing regimens and steroid s.