{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T07:15:54Z","timestamp":1789542954282,"version":"build-2803163510"},"reference-count":23,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2018,10,22]],"date-time":"2018-10-22T00:00:00Z","timestamp":1540166400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2019,3]]},"abstract":"<jats:p>\n                    We present an application of a quantitative systems pharmacology (\n                    <jats:styled-content style=\"fixed-case\">QSP<\/jats:styled-content>\n                    ) model to support a regulatory decision, specifically in assessing the adequacy of the proposed dosing regimen. On January 23, 2015, the US Food and Drug Administration (\n                    <jats:styled-content style=\"fixed-case\">FDA<\/jats:styled-content>\n                    ) approved Natpara (human parathyroid hormone (\n                    <jats:styled-content style=\"fixed-case\">PTH<\/jats:styled-content>\n                    )) to control hypocalcemia in patients with hypoparathyroidism. Clinical trial results indicated that although once\u2010daily\n                    <jats:styled-content style=\"fixed-case\">PTH<\/jats:styled-content>\n                    reduced calcium and vitamin D dose requirement while maintaining the normocalcemia, the regimen was not adequate to control hypercalciuria. We hypothesized that the lack of control on urinary calcium excretion was due to the short half\u2010life of\n                    <jats:styled-content style=\"fixed-case\">PTH<\/jats:styled-content>\n                    . The\n                    <jats:styled-content style=\"fixed-case\">QSP<\/jats:styled-content>\n                    model\u2010based simulations indicated that a more frequent dosing regimen may provide better control on hypercalciuria while maintaining normocalcemia. A postmarketing trial was recommended to assess pharmacokinetics (PKs) and pharmacodynamics (PDs) of\n                    <jats:styled-content style=\"fixed-case\">PTH<\/jats:styled-content>\n                    dose and dosing regimen. Although other modeling approaches may be feasible, in this specific case,\n                    <jats:styled-content style=\"fixed-case\">QSP<\/jats:styled-content>\n                    model\u2010based simulations fulfilled the information gap to support recommendations of this postmarketing trial.\n                  <\/jats:p>","DOI":"10.1002\/cpt.1200","type":"journal-article","created":{"date-parts":[[2018,10,22]],"date-time":"2018-10-22T22:28:50Z","timestamp":1540247330000},"page":"710-718","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Use of a Systems Pharmacology Model Based Approach Toward Dose Optimization of Parathyroid Hormone Therapy in Hypoparathyroidism"],"prefix":"10.1111","volume":"105","author":[{"given":"Manoj","family":"Khurana","sequence":"first","affiliation":[{"name":"Office of Clinical Pharmacology Center for Drug Evaluation and Research US Food and Drug Administration (FDA)  Silver Spring Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Immo","family":"Zadezensky","sequence":"additional","affiliation":[{"name":"EMD Serono  Washington DC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi","family":"Lowy","sequence":"additional","affiliation":[{"name":"Office of New Drugs Center for Drug Evaluation and Research US Food and Drug Administration (FDA)  Silver Spring Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dragos","family":"Roman","sequence":"additional","affiliation":[{"name":"Office of New Drugs Center for Drug Evaluation and Research US Food and Drug Administration (FDA)  Silver Spring Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean\u2010Marc","family":"Guettier","sequence":"additional","affiliation":[{"name":"Sanofi\u2010Aventis Deutschland GmbH Industriepark Hoechst  Frankfurt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Li","sequence":"additional","affiliation":[{"name":"Office of Clinical Pharmacology Center for Drug Evaluation and Research US Food and Drug Administration (FDA)  Silver Spring Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffry","family":"Florian","sequence":"additional","affiliation":[{"name":"Office of New Drugs Center for Drug Evaluation and Research US Food and Drug Administration (FDA)  Silver Spring Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandrahas G.","family":"Sahajwalla","sequence":"additional","affiliation":[{"name":"Office of Clinical Pharmacology Center for Drug Evaluation and Research US Food and Drug Administration (FDA)  Silver Spring Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikram","family":"Sinha","sequence":"additional","affiliation":[{"name":"Merck &amp; Co  North Wales Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nitin","family":"Mehrotra","sequence":"additional","affiliation":[{"name":"Merck &amp; Co  North Wales Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,10,22]]},"reference":[{"key":"e_1_2_10_1_1","unstructured":"Quantitative and systems pharmacology in the post\u2010genomic era: new approaches to discovering drugs and understanding therapeutic mechanisms. <https:\/\/www.nigms.nih.gov\/training\/documents\/systemspharmawpsorger2011.pdf>."},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.me.32.020181.002325"},{"key":"e_1_2_10_3_1","unstructured":"BLA125511 (Natpara\u00ae) FDA Label. <https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2015\/125511s000lbl.pdf>."},{"key":"e_1_2_10_4_1","unstructured":"BLA125511 FDA Medical Officer Review(page 48 of 169). <https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2015\/125511Orig1s000MedR.pdf>."},{"key":"e_1_2_10_5_1","article-title":"PK in late phase trials: collecting PK data in late phase trials led to alleviating additional trials, drug approval, and better dosing","volume":"21","author":"Wang Y.","year":"2012","journal-title":"Applied Clinical Trials"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2009.08.053"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.470"},{"key":"e_1_2_10_8_1","unstructured":"BLA125511 FDA Clinical Pharmacology Review. <http:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2015\/125511Orig1s000ClinPharmR.pdf>."},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-012290421-9\/50010-X"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2002-011870"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12020-011-9521-y"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-9877(03)00107-5"},{"key":"e_1_2_10_13_1","first-page":"R664","article-title":"Simulation of calcium homeostasis: modeling and parameter estimation","volume":"245","author":"Hurwitz S.","year":"1983","journal-title":"Am. 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