The dosing solution influence on the pharmacokinetics of degarelix, a new GnRH antagonist, after s.c. administration to beagle dogs.

OBJECTIVE: Degarelix (FE200486) is a new GnRH-receptor antagonist intended for the treatment of prostate cancer. The objective of the present analysis was to evaluate the pharmacokinetics of degarelix after subcutaneous (s.c.) and intra-muscular (i.m.) administration to male beagle dogs, and to determine the influence of the different dosing conditions on the absorption profile of degarelix.
METHODS: Degarelix was administered to 27 dogs and plasma concentrations were measured. The dosing conditions varied with respect to route (s.c. or i.m.), dose (0.25-1.5 mg/kg), solution strength (1.25-40 mg/ml) and volume administered (0.15-2.9 ml). Data were analysed by use of non-linear mixed effect modelling to characterize the pharmacokinetics, in particular the relationship between dosing conditions and rate, and extent of absorption.
RESULTS: After s.c. and i.m. administration of degarelix, the plasma concentration versus time profile was best described by applying a two-compartment model, with two input functions: a fast first-order input function to describe the rapid initial increase in the plasma concentration levels, and a slow first-order input function to describe the prolonged absorption profile of degarelix. Intra-muscular as opposed to s.c. administration led to a more rapid absorption of degarelix, reaching a mean maximum concentration of 64 and 31 ng/ml roughly 2.0 and 3.7 h after administration, respectively. The slow absorption half-life was found to be 268 h ( approximately 11 days). The relative fraction absorbed was found to vary with the concentration of the dosing solution. The present analysis suggested that the absorbed fraction was reduced by approximately 50% when the concentration in dosing solution was increased from 1.25 to 40 mg/ml. The rate of the initial absorption component was also dependent on the concentration in the dosing solution, with slower absorption at higher concentrations.
CONCLUSION: Through varying the dosing conditions and by applying a joint analysis of all data, the important factors determining the complex absorption of degarelix could be described.