{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T16:26:57Z","timestamp":1759940817484,"version":"3.40.5"},"reference-count":13,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2021,8,25]],"date-time":"2021-08-25T00:00:00Z","timestamp":1629849600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004326","name":"Bayer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004326","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>We report population pharmacokinetic (popPK) and exposure\u2013response (E\u2013R) analyses for efficacy (induced amenorrhoea [IA]) and safety (unbound oestradiol [E2] concentrations) of the selective progesterone receptor modulator vilaprisan. Results were used to inform the dose for the Phase 3 programme in patients with uterine fibroids.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A popPK model was developed using data from Phase 1 and 2 studies (including ASTEROID 1 and 2). The relationship between vilaprisan exposure (steady\u2010state AUC) and IA after oral administration of 0.5, 1, 2 or 4\u00a0mg\/day over 3\u00a0months was analysed in ASTEROID 1 using logistic regression and qualified in ASTEROID 2 by comparing simulated and observed probability for IA after 2\u00a0mg\/day. The exposure\u2013E2 relationship was analysed visually.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Vilaprisan clearance was 22.7% lower in obese <jats:italic>vs<\/jats:italic> non\u2010obese patients. The E\u2013R relationship for IA in ASTEROID 1 was steep and consistent with ASTEROID 2, with a maximum probability (<jats:italic>P<\/jats:italic><jats:sub>max<\/jats:sub>) of 59% (95% CI: 49\u201368%). The exposure at which 50% of <jats:italic>P<\/jats:italic><jats:sub>max<\/jats:sub> is obtained was 36.9\u00a0\u03bcg*h\/L (95% CI: 27.7\u201348.7\u00a0\u03bcg*h\/L). Simulations showed that 36% of the patients will be below 90% of <jats:italic>P<\/jats:italic><jats:sub>max<\/jats:sub> for IA after 1\u00a0mg\/day compared to 2% after 2\u00a0mg\/day. E2 levels tended to decrease with increasing exposure. While E2 levels remained largely within the physiologic follicular phase range, the clinical relevance of this decrease will be evaluated in long\u2010term studies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>A 2\u00a0mg\/day dose was selected for Phase 3 as E\u2013R analyses show this dose results in a close to maximum probability for IA, without any safety concerns noted.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.15014","type":"journal-article","created":{"date-parts":[[2021,7,30]],"date-time":"2021-07-30T07:41:09Z","timestamp":1627630869000},"page":"734-741","source":"Crossref","is-referenced-by-count":7,"title":["Assessment of the safe and efficacious dose of the selective progesterone receptor modulator vilaprisan for the treatment of patients with uterine fibroids by exposure\u2013response modelling and simulation"],"prefix":"10.1111","volume":"88","author":[{"given":"Gabriele","family":"Sutter","sequence":"first","affiliation":[{"name":"Bayer AG, Clinical Pharmacometrics  Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Frei","sequence":"additional","affiliation":[{"name":"Bayer AG, Clinical Pharmacometrics  Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4424-6339","authenticated-orcid":false,"given":"Marcus\u2010Hillert","family":"Schultze\u2010Mosgau","sequence":"additional","affiliation":[{"name":"Bayer AG, Clinical Pharmacology  Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathrin","family":"Petersdorf","sequence":"additional","affiliation":[{"name":"Bayer AG, Pediatric Development  Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Seitz","sequence":"additional","affiliation":[{"name":"Bayer AG, Clinical Development  Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1183-7458","authenticated-orcid":false,"given":"Bart A.","family":"Ploeger","sequence":"additional","affiliation":[{"name":"Bayer AG, Clinical Pharmacometrics  Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,8,25]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1067\/mob.2003.99"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/1471-0528.14640"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.contraception.2009.12.012"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/det247"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.5414\/CP202756"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.998"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dew140"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2018.10.012"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejogrb.2020.05.043"},{"key":"e_1_2_11_11_1","unstructured":"Roche.Elecsys Estradiol III. 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Accessed on 27 May 2021."},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-017-0607-4"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.2165\/11599410-000000000-00000"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2016.06.012"}],"container-title":["British Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bcp.15014","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/bcp.15014","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bcp.15014","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T04:11:59Z","timestamp":1692850319000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bcp.15014"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,25]]},"references-count":13,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2022,2]]}},"alternative-id":["10.1111\/bcp.15014"],"URL":"https:\/\/doi.org\/10.1111\/bcp.15014","archive":["Portico"],"relation":{},"ISSN":["0306-5251","1365-2125"],"issn-type":[{"type":"print","value":"0306-5251"},{"type":"electronic","value":"1365-2125"}],"subject":[],"published":{"date-parts":[[2021,8,25]]}}}