Population pharmacokinetic/pharmacodynamic (PK/PD) modelling of the hypothalamic-pituitary-gonadal axis following treatment with GnRH analogues.
OBJECTIVE
To develop a population pharmacokinetic/pharmacodynamic (PK/PD) model of the hypothalamic-pituitary-gonadal (HPG) axis describing the changes in luteinizing hormone (LH) and testosterone concentrations following treatment with the gonadotropin-releasing hormone (GnRH) agonist triptorelin and the GnRH receptor blocker degarelix.


METHODS
Fifty-eight healthy subjects received single subcutaneous or intramuscular injections of 3.75 mg of triptorelin and 170 prostate cancer patients received multiple subcutaneous doses of degarelix of between 120 and 320 mg. All subjects were pooled for the population PK/PD data analysis. A systematic population PK/PD model-building framework using stochastic differential equations was applied to the data to identify nonlinear dynamic dependencies and to deconvolve the functional feedback interactions of the HPG axis.


RESULTS
In our final PK/PD model of the HPG axis, the half-life of LH was estimated to be 1.3 h and that of testosterone 7.69 h, which corresponds well with literature values. The estimated potency of LH with respect to testosterone secretion was 5.18 IU l(-1), with a maximal stimulation of 77.5 times basal testosterone production. The estimated maximal triptorelin stimulation of the basal LH pool release was 1330 times above basal concentrations, with a potency of 0.047 ng ml(-1). The LH pool release was decreased by a maximum of 94.2% by degarelix with an estimated potency of 1.49 ng ml(-1).


CONCLUSIONS
Our model of the HPG axis was able to account for the different dynamic responses observed after administration of both GnRH agonists and GnRH receptor blockers, suggesting that the model adequately characterizes the underlying physiology of the endocrine system.
Tornøe
Christoffer W
CW
Experimental Medicine, Ferring Pharmaceuticals A/S, Copenhagen, Denmark. christoffer.tornoe@fda.hhs.gov
Agersø
Henrik
H
Senderovitz
Thomas
T
Nielsen
Henrik A
HA
Madsen
Henrik
H
Karlsson
Mats O
MO
Jonsson
E Niclas
EN
D004305:Dose-Response Relationship, Drug; D025461:Feedback, Physiological; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007986:Luteinizing Hormone / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D009842:Oligopeptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D010902:Pituitary Gland; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors*; D013739:Testosterone / Q000378:metabolism*; D017329:Triptorelin Pamoate / Q000493:pharmacokinetics / Q000494:pharmacology*
D009842:Oligopeptides; D011966:Receptors, LHRH; C431566:acetyl-2-naphthylalanyl-3-chlorophenylalanyl-1-oxohexadecyl-seryl-4-aminophenylalanyl(hydroorotyl)-4-aminophenylalanyl(carbamoyl)-leucyl-ILys-prolyl-alaninamide; D017329:Triptorelin Pamoate; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D007986:Luteinizing Hormone