Ulrika S.H. Simonsson, Thomas Senderovitz and Mats O. Karlsson
Uppsala University, Sweden and Ferring Pharmaceutical A/S, Denmark
The aim was to describe the response to degarelix, a GnRH antagonist for prostate cancer using nonlinear mixed effects modeling of data from 60 subjects. Degarelix showed flip-flop PK with a long terminal half-life (47 days). A mechanism-based model for the degarelix/LH/T interaction included competitive antagonism of degarelix (estimated Ki= 0.0642 ng/ml) with an endogenous agonist (EA) for GnRH receptors. Production rate of LH was linked to the fraction activated receptors through a spare receptor model (R50=0.20, baseline [EA]/[EA]50= 0.39). A continuous suppression of LH/T led to receptor down-regulation, in the model estimated to a 93% decrease of receptor density at full suppression of T and a receptor mean residence time (MRT) of 4.5 days. A turn-over model described the conversion of T to DHT with a MRT of 6.2 hours. Through a mechanism-based model, the complex interplay could be described and potentially used for prediction.
Reference: PAGE 12 (2003) Abstr 442 [www.page-meeting.org/?abstract=442]
Poster: poster