Wang Zhenlei, Chen Li, Zhang Fengkui, Lu Hua, Chen Xiequn, Wen Aidong, Luo Jianmin, Hu Yu, Wang Yongsheng, Niu Ting, Zheng Li
GCP Center/National Institute of Drug Clinical Trial, West China Hospital of Sichuan University, Chengdu, China.
Department of Hematology, Institute of Hematology & Blood Diseases Hospital, Tianjin, China.
J Thromb Haemost. 2020 Nov;18(11):3053-3060. doi: 10.1111/jth.15078. Epub 2020 Oct 1.
Idiopathic thrombocytopenic purpura (ITP) especially refractory and (or) relapsed ITP, is a serious and global health burden and its clinical treatment is far from being satisfied. Hetrombopag is a novel, small-molecule thrombopoietin receptor agonist for the treatment of chronic idiopathic thrombocytopenic purpura (CITP).
This first-in-patient study aimed to investigate the safety, pharmacokinetics, and anticipated therapeutic dose of hetrombopag in CITP patients.
In this multicenter, first-in-patient study, CITP patients received hetrombopag in a dose escalation (2.5 mg/day, 5 mg/day, or 7.5 mg/day) cohort. All patients received hetrombopag in fasting condition once daily for 2 weeks.
Of 44 patients screened, 32 were enrolled and treated. Most adverse events were graded 1 to 2 (ie, mild to moderate), and the incidence and severity were similar for three study cohorts. The pharmacokinetics of hetrombopag were found to be nonlinear with greater than dose-proportional: 12.5% of patients (1/8) in the 2.5 mg/d cohort, 58.3% of patients (7/12) in the 5 mg/d cohort, 66.7% of patients (8/12) in the 7.5 mg/d cohort reached the primary study endpoint of a platelet count exceeding 50 × 10 /L on day 28.
Hetrombopag was well tolerated and preliminarily efficacious. Efficacy, safety, and pharmacokinetic data suggest that 7.5 mg hetrombopag once daily was the anticipated therapeutic dose of hetrombopag in CITP patients and has been recommended for investigation in a later confirmatory clinical study of hetrombopag.
特发性血小板减少性紫癜（ITP），尤其是难治性和（或）复发性ITP，是一项严重的全球性健康负担，其临床治疗远不能令人满意。海曲泊帕是一种新型小分子血小板生成素受体激动剂，用于治疗慢性特发性血小板减少性紫癜（CITP）。
这项首次在患者中开展的研究旨在调查海曲泊帕在CITP患者中的安全性、药代动力学及预期治疗剂量。
在这项多中心、首次在患者中开展的研究中，CITP患者按剂量递增队列（2.5毫克/天、5毫克/天或7.5毫克/天）接受海曲泊帕治疗。所有患者在空腹状态下每天接受一次海曲泊帕治疗，持续2周。
在44例筛选的患者中，32例入组并接受治疗。大多数不良事件为1至2级（即轻度至中度），三个研究队列的发生率和严重程度相似。发现海曲泊帕的药代动力学呈非线性，且大于剂量比例关系：2.5毫克/天队列中12.5%的患者（1/8）、5毫克/天队列中58.3%的患者（7/12）、7.5毫克/天队列中66.7%的患者（8/12）在第28天达到血小板计数超过50×10⁹/L的主要研究终点。
海曲泊帕耐受性良好且初步有效。疗效、安全性和药代动力学数据表明，每天一次7.5毫克海曲泊帕是CITP患者中海曲泊帕的预期治疗剂量，并已被推荐用于后续海曲泊帕的确证性临床研究中进行调查。
