Semi-mechanistic pharmacodynamic modeling for degarelix, a novel gonadotropin releasing hormone (GnRH) blocker.
An integrated semi-mechanistic pharmacodynamic (PD) model describing the relationship between luteinizing hormone (LH) and testosterone (T) after short-term administration of degarelix was developed. Data from three clinical studies involving, intravenous (IV) and subcutaneous (SC) dosing, in healthy male subjects were available. Degarelix pharmacokinetic (PK) data from all studies were modeled simultaneously. One intravenous study was used to develop the PD model and the two other studies (IV and SC dosing) were used to qualify the model. Degarelix PK follows a two-compartment model and exhibits flip-flop kinetics after subcutaneous dosing. Based on physiological mechanism, the gonadotropin releasing hormone (GnRH) time course was described using a pulsatile release model. A precursor-dependent pool model was used to describe the kinetics of LH in the pituitary and plasma compartment. In males, LH regulates T production in leydig cells. Degarelix inhibits the release of LH from the pool compartment to the plasma compartment leading to decreased T production. The plasma half-life of LH (2.6-3.3 hr) and T (2.7 hr) match well with the literature reports. The proposed PD model reasonably described the time course of LH and T including the LH rebound for short-term studies. The model predicted the time course of LH and T for the second IV and SC dosing studies very well. However, the long term simulations from the final model did not match with literature reports. A modification is suggested based on the physiological understanding of the system. The proposed novel modification to precursor models can be of general use for predicting long term responses.
Jadhav
Pravin R
PR
Pharmacometrics, Office of Clinical Pharmacology and Biopharmaceutics, Center for Drug Evaluation and Research, 10903 New Hampshire Avenue, Building 21, Silver Spring, MD 20993, USA.
Agersø
Henrik
H
Tornøe
Christoffer W
CW
Gobburu
Jogarao V S
JV
D000465:Algorithms; D001682:Biological Availability; D002986:Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007986:Luteinizing Hormone / Q000037:antagonists & inhibitors; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D009842:Oligopeptides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013739:Testosterone / Q000037:antagonists & inhibitors
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; D013739:Testosterone; D007986:Luteinizing Hormone