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Safety, pharmacokinetics, and pharmacodynamics of SHR7280, an oral gonadotropin-releasing hormone antagonist in healthy premenopausal women

Affiliation
Phase I Clinical Research Center ,The Affiliated Hospital of Qingdao University ,Qingdao ,China
Xu, Yi;
Affiliation
Department of Clinical Pharmacology ,The Second Hospital of Anhui Medical University ,Hefei ,China
Hu, Wei;
Affiliation
Early Clinical Trial Centre ,The Second Affiliated Hospital of Nanchang University ,Nanchang ,China
Li, Jian;
Affiliation
Phase I Clinical Research Center ,The Affiliated Hospital of Qingdao University ,Qingdao ,China
Jiang, Xin;
Affiliation
Phase I Clinical Research Center ,The Affiliated Hospital of Qingdao University ,Qingdao ,China
Shi, Ping;
Affiliation
Jiangsu Hengrui Pharmaceuticals Co., Ltd. ,Shanghai ,China
Shen, Kai;
Affiliation
Jiangsu Hengrui Pharmaceuticals Co., Ltd. ,Shanghai ,China
Shen, Yu;
Affiliation
Jiangsu Hengrui Pharmaceuticals Co., Ltd. ,Shanghai ,China
Ma, Lingyu;
Affiliation
Phase I Clinical Research Center ,The Affiliated Hospital of Qingdao University ,Qingdao ,China
Cao, Yu

Background: 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. Methods: 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 mg BID) were planned. Safety, PK, and PD parameters were evaluated. Results: SHR7280 presented tolerable toxicity and most adverse events were mild in severity. SHR7280 showed rapid onset of action (median T max ranged from 1.0 to 1.2 h for each dose), and plasma exposure was dose-dependent. PD results showed that SHR7280 300 mg BID and above suppressed estrogen concentration within the estradiol (E 2 ) treatment window for endometriosis (20–50 pg/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 nmol/L). Conclusion: SHR7280 showed favorable safety, PK, and PD profiles in the dose range of 200–500 mg 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. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04554043 , Identifier NCT04554043

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License Holder: Copyright © 2022 Xu, Hu, Li, Jiang, Shi, Shen, Shen, Ma and Cao.

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