@ARTICLE\{IMM2007-05104,
    author       = "C. W. Tornoe and H. Agerso and T. Senderovitz and H. A. Nielsen and H. Madsen and M. O. Karlsson and E. N. Jonsson",
    title        = "Population pharmacokinetic/pharmacodynamic (PK/PD) modelling of the hypothalamic-pituitary-gonadal axis following treatment with GnRH analogues",
    year         = "2007",
    journal      = "British Journal of Clinical Pharmacology",
    volume       = "",
    editor       = "",
    number       = "",
    publisher    = "",
    note         = "Published online: 10-Nov-2006",
    url          = "http://www.blackwell-synergy.com/doi/abs/10.1111/j.1365-2125.2006.02820.x",
    abstract     = "Aims 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."
}