CLINICAL PK PD MODELING AS A TOOL IN DRUG DEVELOPMENT OF CORTICOSTEROIDS/

Corticosteroids are used for the treatment of a variety of different d iseases both locally and systemically. Most therapeutic effects result from glucocorticoid receptor-mediated events, and there seems to be n o substance-specific difference in the post-receptor reaction cascade. Therefore, the extent and duration of glucocorticoid effects depend o nly on the availability of the respective steroid at the receptor site and its affinity to the receptor. This makes glucocorticoids an ideal candidate for PK/PD modelling. Availability at the receptor site is g overned by pharmacokinetic parameters such as bioavailability, clearan ce, protein binding, and volume of distribution. The receptor affinity can easily be measured in vitro. A suitable indirect-response PK/PD m odel is presented that allows description of the receptor-mediated dru g effects such as endogenous cortisol suppression as a function of tim e. Furthermore, this model allows prediction of the systemic activity of newly developed corticosteroids based on their pharmacokinetics and their respective receptor-binding affinity. The model can also be app lied in order to study systemic steroid effects after topical administ ration or to investigate the effect of the time of dosing on cortisol suppression. Comparison of predictions based on this model and results from large clinical studies are in excellent agreement. Corticosteroi ds may represent an ideal class of drugs for the successful use of PK/ PD modelling during drug development allowing to save time and expense s.