Integrated Pharmacometrics and Systems Pharmacology Model‐Based Analyses to Guide GnRH Receptor Modulator Development for Management of Endometriosis
Endometriosis is a gynecological condition resulting from proliferation of endometrial‐like tissue outside the endometrial cavity. Estrogen suppression therapies, mediated through gonadotropin‐releasing hormone (GnRH) modulation, decrease endometriotic implants and diminish associated pain albeit at...
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| description | Endometriosis is a gynecological condition resulting from proliferation of endometrial‐like tissue outside the endometrial cavity. Estrogen suppression therapies, mediated through gonadotropin‐releasing hormone (GnRH) modulation, decrease endometriotic implants and diminish associated pain albeit at the expense of bone mineral density (BMD) loss. Our goal was to provide model‐based guidance for GnRH‐modulating clinical programs intended for endometriosis management. This included developing an estrogen suppression target expected to provide symptomatic relief with minimal BMD loss and to evaluate end points and study durations supportive of efficient development decisions. An existing multiscale model of calcium and bone was adapted to include systematic estrogen pharmacologic effects to describe estrogen concentration‐related effects on BMD. A logistic regression fit to patient‐level data from three clinical GnRH agonist (nafarelin) studies described the relationship of estrogen with endometrial‐related pain. Targeting estradiol between 20 and 40 pg/ml was predicted to provide efficacious endometrial pain response while minimizing BMD effects.
CPT: Pharmacometrics & Systems Pharmacology (2012) 1, e11; doi:10.1038/psp.2012.10; advance online publication 17 October 2012 |
| doi_str_mv | 10.1038/psp.2012.10 |
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CPT: Pharmacometrics & Systems Pharmacology (2012) 1, e11; doi:10.1038/psp.2012.10; advance online publication 17 October 2012</description><subject>Biomarkers</subject><subject>Datasets</subject><subject>Endometriosis</subject><subject>Estrogens</subject><subject>Gynecology</subject><subject>Hormone replacement therapy</subject><subject>Integrated approach</subject><subject>Menopause</subject><subject>Menstruation</subject><subject>Original</subject><subject>Pain</subject><subject>Patients</subject><subject>Pharmacology</subject><subject>Studies</subject><subject>Surgery</subject><subject>Urine</subject><issn>2163-8306</issn><issn>2163-8306</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>BENPR</sourceid><recordid>eNp9kc9u1DAQxi0EotXSE3dkiQsS2uI_Wce5IJVStpWKWLVwtmadyTaVE6d2UpRbH6E33o8nwWHLqnDAF8_o-_nzaD5CXnJ2yJnU77rYHQrGReqekH3BlZxrydTTR_UeOYjxmqWTZ4wX7DnZE1LrXCq5T36ctT1uAvRY0tUVhAasb7APtY0U2pJejrHHJu405zcj_exLdD_v7j9ATM-OWnBjxEh7T5dDXSJdthen9AItdr0PEz04mKqPeIvOdw22Pa0mBVrY4O_WV_SkLbdf-1jHF-RZBS7iwcM9I98-nXw9Pp2ff1meHR-dz222kGyuVY4oeFVBprQtFtnaQlVKoVUhLJQFt3mhhNYAOcoCF7LUmsk8W0uWizztYEbeb327Yd1gadMsAZzpQt1AGI2H2vyttPWV2fhbIxVTRcaSwZsHg-BvBoy9aepo0Tlo0Q_R8IxLrjIpFgl9_Q967YeQtheNEAVLKeoEzsjbLWWDjzFgtRuGMzNlblLmZsp86mbk1eP5d-yfhBMgt8D32uH4Py-zulxlU52EXzTturo</recordid><startdate>201210</startdate><enddate>201210</enddate><creator>Riggs, MM</creator><creator>Bennetts, M</creator><creator>Graaf, PH</creator><creator>Martin, SW</creator><general>John Wiley & Sons, Inc</general><general>Nature Publishing Group</general><scope>24P</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>PHGZM</scope><scope>PHGZT</scope><scope>PIMPY</scope><scope>PKEHL</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201210</creationdate><title>Integrated Pharmacometrics and Systems Pharmacology Model‐Based Analyses to Guide GnRH Receptor Modulator Development for Management of Endometriosis</title><author>Riggs, MM ; Bennetts, M ; Graaf, PH ; Martin, SW</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4530-867ee21ffa468c954bcafd328692cad91c796288aa7e39e53d880374b30727873</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Biomarkers</topic><topic>Datasets</topic><topic>Endometriosis</topic><topic>Estrogens</topic><topic>Gynecology</topic><topic>Hormone replacement therapy</topic><topic>Integrated approach</topic><topic>Menopause</topic><topic>Menstruation</topic><topic>Original</topic><topic>Pain</topic><topic>Patients</topic><topic>Pharmacology</topic><topic>Studies</topic><topic>Surgery</topic><topic>Urine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Riggs, MM</creatorcontrib><creatorcontrib>Bennetts, M</creatorcontrib><creatorcontrib>Graaf, PH</creatorcontrib><creatorcontrib>Martin, SW</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>ProQuest Central (New)</collection><collection>ProQuest One Academic (New)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Middle East (New)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>CPT: pharmacometrics and systems pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Riggs, MM</au><au>Bennetts, M</au><au>Graaf, PH</au><au>Martin, SW</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Integrated Pharmacometrics and Systems Pharmacology Model‐Based Analyses to Guide GnRH Receptor Modulator Development for Management of Endometriosis</atitle><jtitle>CPT: pharmacometrics and systems pharmacology</jtitle><addtitle>CPT Pharmacometrics Syst Pharmacol</addtitle><date>2012-10</date><risdate>2012</risdate><volume>1</volume><issue>10</issue><spage>1</spage><epage>9</epage><pages>1-9</pages><issn>2163-8306</issn><eissn>2163-8306</eissn><abstract>Endometriosis is a gynecological condition resulting from proliferation of endometrial‐like tissue outside the endometrial cavity. Estrogen suppression therapies, mediated through gonadotropin‐releasing hormone (GnRH) modulation, decrease endometriotic implants and diminish associated pain albeit at the expense of bone mineral density (BMD) loss. Our goal was to provide model‐based guidance for GnRH‐modulating clinical programs intended for endometriosis management. This included developing an estrogen suppression target expected to provide symptomatic relief with minimal BMD loss and to evaluate end points and study durations supportive of efficient development decisions. An existing multiscale model of calcium and bone was adapted to include systematic estrogen pharmacologic effects to describe estrogen concentration‐related effects on BMD. A logistic regression fit to patient‐level data from three clinical GnRH agonist (nafarelin) studies described the relationship of estrogen with endometrial‐related pain. Targeting estradiol between 20 and 40 pg/ml was predicted to provide efficacious endometrial pain response while minimizing BMD effects.
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| subjects | Biomarkers Datasets Endometriosis Estrogens Gynecology Hormone replacement therapy Integrated approach Menopause Menstruation Original Pain Patients Pharmacology Studies Surgery Urine |
| title | Integrated Pharmacometrics and Systems Pharmacology Model‐Based Analyses to Guide GnRH Receptor Modulator Development for Management of Endometriosis |
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