Population pharmacokinetic/pharmacodynamic (PK/PD) modelling of the hypothalamic–pituitary–gonadal axis following treatment with GnRH analogues
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 th...
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| Published in | British journal of clinical pharmacology Vol. 63; no. 6; pp. 648 - 664 |
|---|---|
| Main Authors | , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Oxford, UK
Blackwell Publishing Ltd
01.06.2007
Blackwell Science Blackwell Science Inc |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0306-5251 1365-2125 1365-2125 |
| DOI | 10.1111/j.1365-2125.2006.02820.x |
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| 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. |
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| AbstractList | 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.AIMSTo 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.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.METHODSFifty-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.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).RESULTSIn 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).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.CONCLUSIONSOur 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. 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.MethodsFifty-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.ResultsIn 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 .ConclusionsOur 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. 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. 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. 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). 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. 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. |
| Author | Tornøe, Christoffer W. Jonsson, E. Niclas Agersø, Henrik Senderovitz, Thomas Nielsen, Henrik A. Madsen, Henrik Karlsson, Mats O. |
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| Keywords | Antineoplastic agent Pharmacokinetic pharmacodynamic relationship Population pharmacokinetics Agonist Endocrine gland Decapeptide Peptides Central nervous system Gonadotropin RH Hypothalamus Encephalon Degarelix hypothalamic-pituitary-gonadal axis Pituitary gland population PK/PD modelling Antagonist Hormone releasing factor Axis Biological receptor Human GnRH receptor blocker degarelix Pharmacodynamics Biological activity Hypothalamic hormone Treatment Analog Triptorelin systematic PK/PD model building framework GnRH agonist triptorelin NONMEM |
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To develop a population pharmacokinetic/pharmacodynamic (PK/PD) model of the hypothalamic–pituitary–gonadal (HPG) axis describing the changes in... To develop a population pharmacokinetic/pharmacodynamic (PK/PD) model of the hypothalamic-pituitary-gonadal (HPG) axis describing the changes in luteinizing... Aims:To develop a population pharmacokinetic/pharmacodynamic (PK/PD) model of the hypothalamic–pituitary–gonadal (HPG) axis describing the changes in... |
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| SubjectTerms | Biological and medical sciences Dose-Response Relationship, Drug FARMACI Feedback, Physiological GnRH agonist triptorelin GnRH receptor blocker degarelix Gonadotropin-Releasing Hormone - agonists Gonadotropin-Releasing Hormone - pharmacokinetics Gonadotropin-Releasing Hormone - pharmacology Humans Hypothalamic-pituitary-gonadal axis Luteinizing Hormone - secretion Male Medical sciences Models, Biological NONMEM Oligopeptides - pharmacokinetics Oligopeptides - pharmacology Pharmacodynamics Pharmacology. Drug treatments PHARMACY Pituitary Gland Population PK/PD modelling Receptors, LHRH - antagonists & inhibitors Systematic PK/PD model building framework Testosterone - secretion Triptorelin Pamoate - pharmacokinetics Triptorelin Pamoate - pharmacology |
| Title | Population pharmacokinetic/pharmacodynamic (PK/PD) modelling of the hypothalamic–pituitary–gonadal axis following treatment with GnRH analogues |
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