Population pharmacokinetic modeling of a subcutaneous depot for GnRH antagonist degarelix.
OBJECTIVE
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.
Tornøe
Christoffer W
CW
Clinical Pharmacology and Experimental Medicine, Ferring Pharmaceuticals A/S, Copenhagen, Denmark. christoffer.tornoe@ferring.com
Agersø
Henrik
H
Nielsen
Henrik A
HA
Madsen
Henrik
H
Jonsson
E Niclas
EN
D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008954:Models, Biological; D009842:Oligopeptides / Q000008:administration & dosage* / Q000493:pharmacokinetics*
D003692:Delayed-Action Preparations; D009842:Oligopeptides; C431566:acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide; D007987:Gonadotropin-Releasing Hormone