2003
   Verona, Italy

Population Pharmacokinetic Modelling of a Subcutaneous Depot for GnRH Antagonist Degarelix

Christoffer W. Tornøe(1), Henrik Agersø(1), Henrik A. Nielsen(2), Henrik Madsen(2), and E. Niclas Jonsson(3)

(1)Clinical Pharmacology and Experimental Medicine, Ferring Pharmaceuticals; (2)Informatics and Mathematical Modelling, Technical University of Denmark; (3)Department of Pharmaceutical Biosciences, Uppsala University

Objectives: The objective of the present analysis is to develop a population pharmacokinetic model that describes the spontaneous subcutaneous (SC) depot formation of GnRH antagonist degarelix which is being developed for treatment of prostate cancer, exhibiting dose-volume and dose-concentration dependent absorption.

Methods: The pharmacokinetic analysis is made in NONMEM using data from two phase I clinical studies; an intravenous (IV) infusion study and a single SC dose escalation study. A two-compartment disposition model with first-order elimination from the central compartment is used to describe the pharmacokinetics of IV infusion of degarelix. The SC absorption is modelled using an approximation to Ficks' second law of diffusion out of a SC spherical depot. The fraction going into the outer spherical shell is estimated to account for the initial rapid SC release before the depot formation. The dose-volume effect on the SC release profile is modelled using a B-spline basis while the bioavailability is modelled as a function of the dose-concentration.

Results: The SC depot model is approximated by using two concentric spherical compartments where the volume of the outer spherical shell is estimated to approximately 15% of the depot volume. By means of the analytical solution to the partial differential equations of SC diffusion, the discretized compartment model yields sufficiently accurate results of the SC concentration. The estimation of the effective depot volume through the use of a monotone non-decreasing linear B-spline basis indicates that the volume effect is most apparent at low injection volumes while the effect fades out at higher injection volumes. The absolute bioavailability is estimated to decrease at increasing dose-concentrations.

Conclusion: The presented SC depot model describes the complicated pharmacokinetic profile of GnRH antagonist degarelix through joint analysis of IV and SC data. The SC release profile is successfully modelled using the principles of diffusion out of a spherical SC depot with the dose-volume and dose-concentration as controlling factors. This modelling approach might also be applicable for other depot formulated drugs exhibiting complicated pharmacokinetic profiles.