PDF(Pubmed)
Abstract：
Heart failure is the most costly cardiovascular disorder. New treatments are urgently needed. This study aims to evaluate the safety, pharmacokinetics, and pharmacodynamic profile of HEC95468, a soluble guanylate cyclase (sGC) stimulator, in healthy volunteers. Sixty-two, eighteen, and forty-eight participants were enrolled in the single ascending dose (SAD) study, the food effect (FE) study, and the multiple ascending dose (MAD) study, respectively. The study conforms to good clinical practice and the Declaration of Helsinki. Overall, HEC95468 was safe and tolerable; a higher proportion of HEC95468-treated participants reported mild headaches, dizziness, decreased blood pressure, increased heart rate, and gastrointestinal-related treatment-emergent adverse events (TEAEs), similar to the sGC stimulators riociguat and vericiguat. In terms of pharmacokinetic parameters, the maximum observed plasma concentration (Cmax) and the area under the concentration-time curve (AUC0-t) were dose-proportional over the dose range. Moderate accumulation was observed after multiple administrations of HEC95468. Systolic blood pressure (SBP) and diastolic blood pressure decreased, while 3\',5\'-cyclic guanosine monophosphate (cGMP) concentration in plasma increased and heart rate was induced. Vasoactive hormones (renin, angiotensin II, and norepinephrine) in plasma were compensatorily elevated after oral administration. These data supported further clinical trials of HEC95468 in the treatment of heart failure and pulmonary arterial hypertension. Systematic Review Registration: http://www.chinadrugtrials.org.cn, identifier CTR20210064.
摘要：
心力衰竭是最昂贵的心血管疾病。迫切需要新的治疗方法。本研究旨在评估其安全性，药代动力学，和HEC95468，一种可溶性鸟苷酸环化酶（sGC）刺激剂的药效学谱，健康的志愿者六十二，18,48名参与者参加了单次递增剂量（SAD）研究，食物效应(FE)研究，和多次递增剂量(MAD)研究，分别。该研究符合良好的临床实践和赫尔辛基宣言。总的来说,HEC95468是安全且可耐受的；接受HEC95468治疗的参与者中有较高比例的人报告轻度头痛，头晕,血压下降,心率加快,和胃肠道相关治疗引起的不良事件（TEAE），类似于sGC刺激剂riociguat和vericiguat。在药代动力学参数方面，在整个剂量范围内,观察到的最大血浆浓度(Cmax)和浓度-时间曲线下面积(AUC0-t)与剂量成比例.在多次施用HEC95468后观察到适度的积累。收缩压（SBP）和舒张压下降，而3\'，血浆中5'-环磷酸鸟苷（cGMP）浓度增加，并引起心率。血管活性激素（肾素，血管紧张素II，口服后，血浆中的去甲肾上腺素）补偿性升高。这些数据支持HEC95468治疗心力衰竭和肺动脉高压的进一步临床试验。系统审查注册：http://www。chinadrugtrials.org.cn,标识符CTR20210064。
