Optimized therapeutic ratio of inhaled corticosteroids using retrometabolism

During recent years, the treatment of pulmonary diseases could be significa ntly improved due to the introduction of modern retrometabolism-based corti costeroids with improved therapeutic ratio. It is the goal of all inhaled c orticosteroids to produce long lasting therapeutic effects at the pulmonary target site and to minimize systemic side effects by rapid clearance of th e absorbed drug and low oral bioavailability. The development of PK/PD mode ls allows predictions of drug effects based on the administered dose. For e xample, the cumulative suppression of endogenous cortisol release (CCS) as one of the major systemic side effects of inhaled corticosteroid therapy ca n be described with an integrated E-max based PK/PD model. In order to asse ss the predictive power of this model, a study was conducted to compare the PK/PD-based predictions with CCS data obtained from actual clinical trials for flunisolide, fluticasone propionate, budesonide and triamcinolone acet onide. CCS was predicted for different single doses from different inhaler devices for each drug and a good correlation was observed. Thus, the presen ted PK/PD model proved to be a valid tool for predicting CCS of inhaled cor ticosteroids. By fully understanding the underlying mechanisms it will be p ossible to further improve their therapeutic index.