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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >First clinical experience with TRV027: Pharmacokinetics and pharmacodynamics in healthy volunteers
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First clinical experience with TRV027: Pharmacokinetics and pharmacodynamics in healthy volunteers

机译：TRV027的首次临床经验：健康志愿者的药代动力学和药效学

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摘要

TRV027 is a novel β-arrestin biased peptide ligand of the angiotensin II type 1 receptor (AT1R). The compound antagonizes G protein coupling while simultaneously stimulating β-arrestin-mediated signaling. In preclinical studies, TRV027 reversibly reduced blood pressure while preserving renal function in a dog tachypaced heart failure model and stimulating cardiomyocyte contractility in vitro. This profile suggests that TRV027 may have unique benefits in acute heart failure, a condition associated with renin-angiotensin system activation.A first-time-in-human study was conducted with ascending doses of TRV027 to explore its tolerability, pharmacokinetics and pharmacodynamics in healthy volunteers. Subjects' salt intake was restricted to stimulate RAS activation. In this study TRV027 was safe and well tolerated with a short-half-life (ranging between 2.4 and 13.2 minutes) and doseproportional increases in systemic exposure. Consistent with the pre-clinical findings, TRV027 reduced blood pressure to a greater degree in subjects with RAS activation, measured as elevated plasma renin activity, than in those with normal PRA levels. This study in sodium-restricted healthy subjects suggests that TRV027 will successfully target a core mechanism of acute heart failure pathophysiology. Further clinical studies with TRV027 in patients with heart failure are underway.
机译：TRV027是血管紧张素II 1型受体（AT1R）的新型β-arrestin偏向肽配体。该化合物拮抗G蛋白偶联，同时刺激β-arrestin介导的信号传导。在临床前研究中，TRV027可逆地降低了血压，同时在狗心动过速的心衰模型中保留了肾功能，并在体外刺激了心肌细胞的收缩性。该概况表明TRV027在急性心力衰竭（与肾素-血管紧张素系统激活有关的疾病）中可能具有独特的益处。首次人体研究以增加剂量的TRV027进行，以探索其在健康中的耐受性，药代动力学和药效学志愿者。限制受试者的盐摄入以刺激RAS激活。在这项研究中，TRV027安全且耐受性好，半衰期短（介于2.4和13.2分钟之间），并且全身暴露剂量呈比例增加。与临床前的发现一致，与血浆PRA水平正常的患者相比，TRV027在具有RAS活化作用的受试者（以血浆肾素活性升高衡量）中将血压降低的程度更大。钠受限健康受试者的这项研究表明，TRV027将成功靶向急性心力衰竭病理生理学的核心机制。 TRV027在心力衰竭患者中的​​进一步临床研究正在进行中。

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