Safety, Pharmacokinetics, and Pharmacodynamics of SHR7280, a Non-peptide GnRH Antagonist in Premenopausal Women with Endometriosis: A Randomized, Double-Blind, Placebo-Controlled Phase 1 Study.

IF 4.6 2区医学 Q1 PHARMACOLOGY & PHARMACY Clinical Pharmacokinetics Pub Date : 2023-12-01 Epub Date: 2023-10-14 DOI:10.1007/s40262-023-01315-6

Yuan Li, Ying Zheng, Bing Xu, Linrui Cai, Sheng Feng, Yiming Liu, Zhenyi Zhu, Qin Yu, Hongyan Guo

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Abstract

Background: Oral gonadotropin-releasing hormone (GnRH) antagonists are promising agents in the treatment of endometriosis-related pain. Here we assessed the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of SHR7280, an oral non-peptide GnRH antagonist in premenopausal women with endometriosis.

Methods: In the Phase 1 part of the randomized, double-blinded, placebo-controlled, dose-ascending, Phase 1/2 trial, premenopausal women with endometriosis were randomized (4:1) to receive SHR7280 or placebo treatment for 21 consecutive days. The treatment dose started from 200 mg QD, and then increased to 300 mg QD and 200 mg BID. Safety, PK, and PD parameters were assessed.

Results: In total, 30 patients received assigned treatment, 24 with SHR7280 and 6 with placebo. SHR7280 was well tolerated. Adverse events (AEs) were reported in 19 (79.2%, 19/24) patients in the SHR7280 group and 5 (83.3%, 5/6) patients in the placebo group. Most AEs were mild and no severe AEs occurred. SHR7280 showed a rapid absorption, with a time to maximum plasma concentration (T_max) of 1.0 h, 1.0 h, and 0.8 h for the 200 mg QD, 300 mg QD, and 200 mg BID regimens, respectively. Plasma concentration of SHR7280 was dose dependent. The mean half-life (t_1/2) at steady state was 6.9 h, 7.4 h, and 2.8 h, respectively, and little or no accumulation was observed. Pharmacodynamic analysis showed that SHR7280 could effectively suppress estradiol and luteinizing hormone concentrations and prevent progesterone increase in a dose-dependent manner. SHR7280 at doses of 300 mg QD and 200 mg BID could suppress estradiol levels within the desired therapeutic window of 20-50 pg/mL throughout the treatment period.

Conclusions: SHR7280 showed favorable safety, PK, and PD profiles in the doses of 200 mg QD, 300 mg QD, and 200 mg BID. The results of this study provide evidence to support the further development of SHR7280 as a GnRH antagonist for the treatment of endometriosis-related pain in the subsequent Phase 2 trial.

Trial registry: Trial registration number: Clinicaltrials.gov, identifier: NCT04417972. Trial registration date: 5 June 2020.

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SHR7280是一种非肽GnRH拮抗剂，用于绝经前子宫内膜异位症妇女的安全性、药代动力学和药效学：一项随机、双盲、安慰剂对照的1期研究。

背景：口服促性腺激素释放激素（GnRH）拮抗剂是治疗子宫内膜异位症相关疼痛的有前途的药物。在这里，我们评估了SHR7280的安全性、药代动力学（PK）和药效学（PD），SHR7280是一种口服非肽GnRH拮抗剂，用于绝经前子宫内膜异位症妇女。方法：在随机、双盲、安慰剂对照、剂量递增的1/2期试验的1期部分，将患有子宫内膜异位症的绝经前妇女随机（4:1）接受SHR7280或安慰剂治疗，连续21天。治疗剂量从200 mg QD开始，然后增加到300 mg QD和200 mg BID。评估安全性、PK和PD参数。结果：总共有30名患者接受了指定的治疗，其中24名接受了SHR7280治疗，6名接受了安慰剂治疗。SHR7280耐受性良好。SHR7280组有19名（79.2%，19/24）患者和安慰剂组有5名（83.3%，5/6）患者报告了不良事件（AE）。大多数不良事件为轻度，未发生严重不良事件。SHR7280表现出快速吸收，200 mg QD、300 mg QD和200 mg BID方案的达到最大血浆浓度的时间（Tmax）分别为1.0小时、1.0小时和0.8小时。SHR7280的血浆浓度呈剂量依赖性。稳态下的平均半衰期（t1/2）分别为6.9小时、7.4小时和2.8小时，观察到很少或没有积累。药效学分析表明，SHR7280能有效抑制雌二醇和黄体生成素的浓度，并以剂量依赖的方式阻止孕酮的增加。在整个治疗期间，300 mg QD和200 mg BID剂量的SHR7280可以在20-50 pg/mL的期望治疗窗口内抑制雌二醇水平。结论：SHR7280在200 mg QD、300 mg QD和200 mg BID剂量下显示出良好的安全性、PK和PD特征。本研究的结果为在随后的2期试验中进一步开发SHR7280作为GnRH拮抗剂治疗子宫内膜异位症相关疼痛提供了证据。试验注册处：试验注册号：Clinicaltrials.gov，标识符：NCT04417972。试验注册日期：2020年6月5日。

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来源期刊

Clinical Pharmacokinetics 医学-药学

CiteScore

8.80

自引率

4.40%

发文量

审稿时长

6-12 weeks

期刊介绍： Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics. Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.