Premium
First Clinical Experience with TRV027: Pharmacokinetics and Pharmacodynamics in Healthy Volunteers
Author(s) -
Soergel David G.,
Subach Ruth Ann,
Cowan Conrad L.,
Violin Jonathan D.,
Lark Michael W.
Publication year - 2013
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.111
Subject(s) - medicine , pharmacokinetics , heart failure , tolerability , pharmacodynamics , blood pressure , pharmacology , renin–angiotensin system , contractility , angiotensin ii , plasma renin activity , heart rate , endocrinology , adverse effect
Abstract 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 dose‐proportional 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.