Integrated Pharmacometrics and Systems Pharmacology Model‐Based Analyses to Guide GnRH Receptor Modulator Development for Management of Endometriosis

Riggs, Matthew M.; Bennetts, Meg; Graaf, Piet H. van der; Martin, Steven W.

doi:10.1038/psp.2012.10

Cited by 35 publications

(53 citation statements)

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“…This exercise suggested that inhibitors of TrkA kinase may be an interesting approach for novel pain medications, but highlights that achieving saturating inhibition may require higher unbound plasma drug concentrations than might be expected according to simple pharmacological theory. Data-validated systems pharmacology models such as described in this study (and in other areas such as central nervous system diseases [33], oncology [34], osteoporosis [35], endometriosis [9] and safety [36]) could be of great utility in drug discovery.…”

Section: Resultsmentioning

confidence: 99%

“…This has been most notably applied in academic research where systems biology has become a mainstream feature of research and funding priorities [7]. This is also being explored within the pharmaceutical industry [8][9][10]. The purpose of the work described in this study was to explore the utility of systems modelling approaches in the context of the NGF pathway, to extract relevant conclusions and to suggest optimal ways to test these experimentally.…”

Section: Introductionmentioning

confidence: 99%

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Systems pharmacology of the nerve growth factor pathway: use of a systems biology model for the identification of key drug targets using sensitivity analysis and the integration of physiology and pharmacology

et al. 2013

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ResearchCite this article: Benson N, Matsuura T, Smirnov S, Demin O, Jones HM, Dua P, van der Graaf PH. 2013 Systems pharmacology of the nerve growth factor pathway: use of a systems biology model for the identification of key drug targets using sensitivity analysis and the integration of physiology and pharmacology. The nerve growth factor (NGF) pathway is of great interest as a potential source of drug targets, for example in the management of certain types of pain. However, selecting targets from this pathway either by intuition or by non-contextual measures is likely to be challenging. An alternative approach is to construct a mathematical model of the system and via sensitivity analysis rank order the targets in the known pathway, with respect to an endpoint such as the diphosphorylated extracellular signal-regulated kinase concentration in the nucleus. Using the published literature, a model was created and, via sensitivity analysis, it was concluded that, after NGF itself, tropomyosin receptor kinase A (TrkA) was one of the most sensitive druggable targets. This initial model was subsequently used to develop a further model incorporating physiological and pharmacological parameters. This allowed the exploration of the characteristics required for a successful hypothetical TrkA inhibitor. Using these systems models, we were able to identify candidates for the optimal drug targets in the known pathway. These conclusions were consistent with clinical and human genetic data. We also found that incorporating appropriate physiological context was essential to drawing accurate conclusions about important parameters such as the drug dose required to give pathway inhibition. Furthermore, the importance of the concentration of key reactants such as TrkA kinase means that appropriate contextual data are required before clear conclusions can be drawn. Such models could be of great utility in selecting optimal targets and in the clinical evaluation of novel drugs.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Systems pharmacology of the nerve growth factor pathway: use of a systems biology model for the identification of key drug targets using sensitivity analysis and the integration of physiology and pharmacology

et al. 2013

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“…The group of Peterson and Riggs have published a physiology‐based mathematical representation of integrated calcium homeostasis and bone remodeling, which they later extended to show nonlinear changes in lumbar spine (LS) bone mineral density (BMD) upon denosumab treatment, a monoclonal antibody that decreases bone resorption, and to describe the impact of progressive loss of kidney function . This group has also described estrogen‐related changes in bone and calcium balance through menopause transition with an extension to fracture risks . In their current form these extensive physiology‐based models are challenging to apply in a population approach, which captures the existing variability in addition to the structural dynamics.…”

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confidence: 99%

Application of a Systems Pharmacology‐Based Placebo Population Model to Analyze Long‐Term Data of Postmenopausal Osteoporosis

Berkhout

Stone

Verhamme³

et al. 2015

CPT Pharmacometrics Syst. Pharmacol.

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Osteoporosis is a progressive bone disease characterized by decreased bone mass resulting in increased fracture risk. The objective of this investigation was to test whether a recently developed disease systems analysis model for osteoporosis could describe disease progression in a placebo-treated population from the Early Postmenopausal Intervention Cohort (EPIC) study. First, we qualified the model using a subset from the placebo arm of the EPIC study of 222 women who had similar demographic characteristics as the 149 women from the placebo arm of the original population. Second, we applied the model to all 470 women. Bone mineral density (BMD) dynamics were changed to an indirect response model to describe lumbar spine and total hip BMD in this second population. This updated disease systems analysis placebo model describes the dynamics of all biomarkers in the corresponding datasets to a very good approximation; a good description of an individual placebo response will be valuable for evaluating treatments for osteoporosis.

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“…However, the approved duration of use of GnRH modulators is restricted due to their castrating effects and consequent menopausal-like adverse events, including loss of bone mineral density and incidences of hot flashes (2). Therefore, alternative approaches that offer a more refined modulation of the HPG axis would be of therapeutic benefit.…”

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confidence: 99%

The NK3 Receptor Antagonist ESN364 Interrupts Pulsatile LH Secretion and Moderates Levels of Ovarian Hormones Throughout the Menstrual Cycle

et al. 2015

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Women's health disorders such as uterine fibroids and endometriosis are currently treated by GnRH modulators that effectively suppress the hypothalamic-pituitary-gonadal axis. The neurokinin-3 receptor (NK3R) is an alternative target with an important role in the modulation of this axis. In this report, we demonstrate that systemic administration of an NK3R antagonist (ESN364) prolongs the LH interpulse interval in ovarectomized ewes and significantly lowers plasma LH and FSH concentrations in castrated nonhuman primates (Macaca fascicularis). Moreover, daily oral dosing of ESN364 throughout the menstrual cycle in M fascicularis lowered plasma estradiol levels in a dose-dependent manner, although nadir levels of estradiol were maintained well above menopausal levels. Nevertheless, estradiol levels during the follicular phase were sufficiently inhibited at all doses to preclude the triggering of ovulation as evidenced by the absence of the LH surge and failure of a subsequent luteal phase rise in plasma progesterone concentrations, consistent with the absence of normal cycle changes in the uterus. Apart from the point at surge, FSH levels were not altered over the course of the menstrual cycle. These effects of ESN364 were reversible upon cessation of drug treatment. Together these data support the proposed role of neurokinin B-NK3R signaling in the control of pulsatile GnRH secretion. Furthermore, in contrast to GnRH antagonists, NK3R antagonists induce a partial suppression of estradiol and thereby offer a viable therapeutic approach to the treatment of ovarian sex hormone disorders with a mitigated risk of menopausallike adverse events in response to long-term drug exposure. (Endocrinology 156: 4214 -4225, 2015)

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Integrated Pharmacometrics and Systems Pharmacology Model‐Based Analyses to Guide GnRH Receptor Modulator Development for Management of Endometriosis

Cited by 35 publications

References 47 publications

Systems pharmacology of the nerve growth factor pathway: use of a systems biology model for the identification of key drug targets using sensitivity analysis and the integration of physiology and pharmacology

Systems pharmacology of the nerve growth factor pathway: use of a systems biology model for the identification of key drug targets using sensitivity analysis and the integration of physiology and pharmacology

Application of a Systems Pharmacology‐Based Placebo Population Model to Analyze Long‐Term Data of Postmenopausal Osteoporosis

The NK3 Receptor Antagonist ESN364 Interrupts Pulsatile LH Secretion and Moderates Levels of Ovarian Hormones Throughout the Menstrual Cycle

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