Clinical PK/PD modelling as a tool in drug development of corticosteroids.
Corticosteroids are used for the treatment of a variety of different diseases both locally and systemically. Most therapeutic effects result from glucocorticoid receptor-mediated events, and there seems to be no substance-specific difference in the post-receptor reaction cascade. Therefore, the extent and duration of glucocorticoid effects depend only 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 governed by pharmacokinetic parameters such as bioavailability, clearance, protein binding, and volume of distribution. The receptor affinity can easily be measured in vitro. A suitable indirect-response PK/PD model is presented that allows description of the receptor-mediated drug effects such as endogenous cortisol suppression as a function of time. 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 applied in order to study systemic steroid effects after topical administration 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. Corticosteroids may represent an ideal class of drugs for the successful use of PK/PD modelling during drug development allowing to save time and expenses.
Derendorf
H
H
College of Pharmacy, University of Florida, Gainesville 32610, USA.
Möllmann
H
H
Hochhaus
G
G
Meibohm
B
B
Barth
J
J
D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D018655:Lymphocyte Count / Q000187:drug effects; D008954:Models, Biological; D011237:Predictive Value of Tests; D011485:Protein Binding; D013601:T-Lymphocytes / Q000187:drug effects
D000305:Adrenal Cortex Hormones; D006854:Hydrocortisone