{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T22:16:47Z","timestamp":1767651407597,"version":"3.41.2"},"reference-count":21,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T00:00:00Z","timestamp":1669161600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100018731","name":"Jiangsu Hengrui Medicine","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100018731","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Treatment with gonadotropin-releasing hormone (GnRH) antagonists is a powerful strategy to suppress gonadotropin activity in women with sex hormone-dependent disorders. Herein, we provide the safety, pharmacokinetics (PK), and pharmacodynamics (PD) profiles of SHR7280, an oral non-peptide GnRH antagonist in healthy premenopausal women.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> In this randomized, double-blinded, placebo-controlled, dose-ascending, phase 1 trial, healthy premenopausal women were randomized to receive SHR7280 or placebo orally. Four doses of SHR7280 (200, 300, 400, and 500\u00a0mg BID) were planned. Safety, PK, and PD parameters were evaluated.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> SHR7280 presented tolerable toxicity and most adverse events were mild in severity. SHR7280 showed rapid onset of action (median T<jats:sub>max<\/jats:sub> ranged from 1.0 to 1.2\u00a0h for each dose), and plasma exposure was dose-dependent. PD results showed that SHR7280 300\u00a0mg BID and above suppressed estrogen concentration within the estradiol (E<jats:sub>2<\/jats:sub>) treatment window for endometriosis (20\u201350\u00a0pg\/ml), inhibited the emergence of the peak of luteinizing hormone (LH) and the concentration of follicle stimulating hormone (FSH), and maintained the concentration of progesterone (P) in an anovulatory state (2\u00a0nmol\/L).<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> SHR7280 showed favorable safety, PK, and PD profiles in the dose range of 200\u2013500\u00a0mg BID in healthy premenopausal women. This study supports the continued clinical development of SHR7280 as a GnRH antagonist for sex hormone-dependent disorders in women.<\/jats:p><jats:p><jats:bold>Clinical Trial Registration:<\/jats:bold><jats:ext-link>https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04554043<\/jats:ext-link>, Identifier NCT04554043<\/jats:p>","DOI":"10.3389\/fphar.2022.1027648","type":"journal-article","created":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T05:33:45Z","timestamp":1669181625000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Safety, pharmacokinetics, and pharmacodynamics of SHR7280, an oral gonadotropin-releasing hormone antagonist in healthy premenopausal women"],"prefix":"10.3389","volume":"13","author":[{"given":"Yi","family":"Xu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ping","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai","family":"Shen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Shen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lingyu","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Cao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1016\/j.fertnstert.2017.05.006","article-title":"Elagolix for the management of heavy menstrual bleeding associated with uterine fibroids: results from a phase 2a proof-of-concept study","volume":"108","author":"Archer","year":"2017","journal-title":"Fertil. Steril."},{"key":"B2","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1016\/0002-9378(92)91706-g","article-title":"Hormone treatment of endometriosis: the estrogen threshold hypothesis","volume":"166","author":"Barbieri","year":"1992","journal-title":"Am. J. Obstet. Gynecol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"3331","DOI":"10.1021\/jm701249f","article-title":"Non-peptide gonadotropin-releasing hormone receptor antagonists","volume":"51","author":"Betz","year":"2008","journal-title":"J. Med. Chem."},{"key":"B4","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1016\/s0015-0282(01)01972-0","article-title":"Gonadotropin-releasing hormone antagonists instead of agonists: a change for the better?","volume":"76","author":"Blumenfeld","year":"2001","journal-title":"Fertil. Steril."},{"key":"B5","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/s0015-0282(99)00446-x","article-title":"Gonadotropin-releasing hormone antagonist: new tools vs. old habits","volume":"73","author":"Bouchard","year":"2000","journal-title":"Fertil. Steril."},{"key":"B6","first-page":"153","article-title":"Clinical uses of gonadotropin-releasing hormone analogues","volume":"144","author":"Casper","year":"1991","journal-title":"CMAJ"},{"key":"B7","doi-asserted-by":"publisher","first-page":"CD008018","DOI":"10.1002\/14651858.CD008018.pub3","article-title":"Adjuvant gonadotropin-releasing hormone analogues for the prevention of chemotherapy-induced premature ovarian failure in premenopausal women","volume":"3","author":"Chen","year":"2019","journal-title":"Cochrane Database Syst. Rev."},{"key":"B8","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1056\/NEJM199101103240205","article-title":"Gonadotropin-releasing hormone and its analogues","volume":"324","author":"Conn","year":"1991","journal-title":"N. Engl. J. Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"e27","DOI":"10.1016\/j.fertnstert.2017.07.095","article-title":"Elagolix improves quality of life in women with heavy menstrual bleeding associated with uterine fibroids: evidence from a phase 2B randomized trial","volume":"108","author":"Diamond","year":"2017","journal-title":"Fertil. Steril."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1793","DOI":"10.1016\/S0140-6736(01)06797-6","article-title":"Gonadotropin-releasing-hormone-receptor antagonists","volume":"358","author":"Huirne","year":"2001","journal-title":"Lancet"},{"key":"B11","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1177\/1933719107310707","article-title":"Gonadotropin-releasing hormone in the ovary","volume":"14","author":"Metallinou","year":"2007","journal-title":"Reprod. Sci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1683","DOI":"10.1210\/jc.2016-3845","article-title":"Dose-dependent suppression of gonadotropins and ovarian hormones by elagolix in healthy premenopausal women","volume":"102","author":"Ng","year":"2017","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/s1472-6483(11)60210-1","article-title":"Gonadotrophin-releasing hormone (GnRH) and GnRH agonists: mechanisms of action","volume":"5","author":"Ortmann","year":"2002","journal-title":"Reprod. Biomed. Online"},{"key":"B14","doi-asserted-by":"publisher","first-page":"2066","DOI":"10.1056\/NEJMc2003851","article-title":"Elagolix for fibroid-associated heavy menstrual bleeding. Reply","volume":"382","author":"Schiffman","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1056\/NEJMoa1904351","article-title":"Elagolix for heavy menstrual bleeding in women with uterine fibroids","volume":"382","author":"Schlaff","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1111\/cts.12582","article-title":"Design and conduct considerations for first-in-human trials","volume":"12","author":"Shen","year":"2019","journal-title":"Clin. Transl. Sci."},{"key":"B17","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1210\/jc.2008-1695","article-title":"Suppression of gonadotropins and estradiol in premenopausal women by oral administration of the nonpeptide gonadotropin-releasing hormone antagonist elagolix","volume":"94","author":"Struthers","year":"2009","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"B18","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1097\/AOG.0000000000002675","article-title":"Long-term outcomes of elagolix in women with endometriosis: Results from two extension studies","volume":"132","author":"Surrey","year":"2018","journal-title":"Obstet. Gynecol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1056\/NEJMoa1700089","article-title":"Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist","volume":"377","author":"Taylor","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"B20","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1056\/NEJM197709292971315","article-title":"Gonadotropin-releasing hormone","volume":"297","author":"Valenta","year":"1977","journal-title":"N. Engl. J. Med."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1295","DOI":"10.1007\/s40262-018-0629-6","article-title":"Population pharmacokinetics of elagolix in healthy women and women with endometriosis","volume":"57","author":"Winzenborg","year":"2018","journal-title":"Clin. Pharmacokinet."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.1027648\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T05:33:48Z","timestamp":1669181628000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.1027648\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,23]]},"references-count":21,"alternative-id":["10.3389\/fphar.2022.1027648"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2022.1027648","relation":{},"ISSN":["1663-9812"],"issn-type":[{"type":"electronic","value":"1663-9812"}],"subject":[],"published":{"date-parts":[[2022,11,23]]},"article-number":"1027648"}}