Population Pharmacokinetic Modeling of a Subcutaneous Depot for GnRH Antagonist Degarelix

Purpose. The objective of this study is to develop a population pharmacokinetic (PK) model that describes the subcutaneous (SC) depot formation of gonadotropin-releasing hormone ( GnRH) antagonist degarelix, which is being developed for treatment of prostate cancer, exhibiting dose-volume and dose-concentration dependent absorption.

Methods. The PK analysis is made in NONMEM through joint analysis of data from two phase I clinical studies; an intravenous infusion study and a single SC dose escalation study. The SC absorption is modeled using an approximation to Ficks' second law of diffusion out of a spherical depot. The dose-volume effect on the SC release is estimated using a B-spline basis whereas the bioavailability is modeled as a function of the dose-concentration.

Results. The SC depot model is approximated by using two concentric spherical compartments for the SC absorption combined with a two-compartment disposition model. The results indicate that the volume effect is most apparent at low injection volumes whereas the effect is diminishing at higher injection volumes. The dose-concentration effect on the bioavailability is estimated to decrease at increasing dose-concentrations.

Conclusions. The presented SC depot model describes the PK profile of GnRH antagonist degarelix. This modeling approach might also be applicable for other depot-formulated drugs exhibiting complex PK profiles.