Institute of Clinical Pharmacology, West China Hospital of Sichuan University, Chengdu, China.
Department of Clinical Research, Jiangsu Hengrui Medicine Co., LTD., Shanghai, China.
Basic Clin Pharmacol Toxicol. 2017 Nov;121(5):414-422. doi: 10.1111/bcpt.12815. Epub 2017 Jun 22.
Hetrombopag olamine (hetrombopag) is a novel small-molecule, orally bioavailable, non-peptide thrombopoietin (TPO) receptor agonist that is being developed as the treatment for thrombocytopenia. Two randomized, placebo-controlled phase I studies were conducted in 72 healthy individuals to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of hetrombopag. Hetrombopag was orally administered with a single dose in five dose cohorts (5 mg, 10 mg, 20 mg, 30 mg or 40 mg) in the first study, and given once daily for 10 days in three dose cohorts (2.5 mg, 5.0 mg or 7.5 mg) in the second study, respectively. Hetrombopag was well tolerated, and the majority of adverse events associated with medicine were platelet elevations significantly above the normal range in healthy individuals. The single dose-escalation study revealed a T of approximate 8 hr, and a t of 11.9 hr to 40.1 hr in a dose-prolonged manner. A dose-proportional increase in maximum concentration (C ) of hetrombopag was observed, with area under the curve (AUC) increasing in a greater than dose-proportional manner. The plasma concentration of hetrombopag reached the steady-state after 7 days. The steady-state AUC and C were dose-proportionally elevated from the 5.0 mg to 7.5 mg dose level. The potent pharmacological effect of the hetrombopag-induced platelet elevation was observed in a time- and dose-dependent manner. Furthermore, the thrombopoietic response was significantly (p < 0.0001) correlated to the plasma exposure level of hetrombopag in single and multiple administration studies. Taken together, results of this study support further clinical development of hetrombopag in patients with thrombocytopenia.
奥曲波苷（hetrombopag）是一种新型的小分子、口服生物利用度、非肽类血小板生成素（TPO）受体激动剂，正在开发用于治疗血小板减少症。两项随机、安慰剂对照的 I 期研究在 72 名健康个体中进行，以评估 hetrombopag 的安全性、耐受性、药代动力学和药效学。在第一项研究中，hetrombopag 以单剂量口服给药，分为五个剂量组（5mg、10mg、20mg、30mg 或 40mg）；在第二项研究中，hetrombopag 每天一次给药 10 天，分为三个剂量组（2.5mg、5.0mg 或 7.5mg）。Hetrombopag 耐受性良好，与药物相关的大多数不良事件是血小板升高，明显高于健康个体的正常范围。单次剂量递增研究显示，T 约为 8 小时，在延长剂量时为 11.9 小时至 40.1 小时。观察到 hetrombopag 的最大浓度（C ）呈剂量比例增加，曲线下面积（AUC）呈大于剂量比例增加。Hetrombopag 的血浆浓度在 7 天后达到稳态。在 5.0mg 至 7.5mg 剂量水平，稳态 AUC 和 C 呈剂量比例升高。Hetrombopag 诱导的血小板升高的药效学作用呈时间和剂量依赖性。此外，在单次和多次给药研究中，血小板生成素反应与 hetrombopag 的血浆暴露水平显著相关（p<0.0001）。总之，该研究结果支持在血小板减少症患者中进一步开发奥曲波苷。
