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Pharmacokinetics and Pharmacodynamics of LCZ696, a Novel Dual‐Acting Angiotensin Receptor—Neprilysin Inhibitor (ARNi)
Author(s) -
Gu Jessie,
Noe Adele,
Chandra Priya,
AlFayoumi Suliman,
LiguerosSaylan Monica,
Sarangapani Ramesh,
Maahs Suzanne,
Ksander Gary,
Rigel Dean F.,
Jeng Arco Y.,
Lin TsuHan,
Zheng Weiyi,
Dole William P.
Publication year - 2010
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 - 10.1177/0091270009343932
Subject(s) - valsartan , neprilysin , pharmacology , sacubitril , angiotensin ii , medicine , pharmacokinetics , pharmacodynamics , angiotensin receptor , sacubitril, valsartan , renin–angiotensin system , endocrinology , chemistry , blood pressure , biochemistry , enzyme
Angiotensin receptor blockade and neprilysin (NEP) inhibition together offer potential benefits for the treatment of hypertension and heart failure. LCZ696 is a novel single molecule comprising molecular moieties of valsartan and NEP inhibitor prodrug AHU377 (1:1 ratio). Oral administration of LCZ696 caused dose‐dependent increases in atrial natriuretic peptide immunoreactivity (due to NEP inhibition) in Sprague‐Dawley rats and provided sustained, dose‐dependent blood pressure reductions in hypertensive double‐transgenic rats. In healthy participants, a randomized, double‐blind, placebo‐controlled study (n = 80) of single‐dose (200–1200 mg) and multiple‐dose (50–900 mg once daily for 14 days) oral administration of LCZ696 showed that peak plasma concentrations were reached rapidly for valsartan (1.6–4.9 hours), AHU377 (0.5–1.1 hours), and its active moiety, LBQ657 (1.8–3.5 hours). LCZ696 treatment was associated with increases in plasma cGMP, renin concentration and activity, and angiotensin II, providing evidence for NEP inhibition and angiotensin receptor blockade. In a randomized, open‐label crossover study in healthy participants (n = 56), oral LCZ696 400 mg and valsartan 320 mg were shown to provide similar exposure to valsartan (geometric mean ratio [90% confidence interval]: AUC 0‐∞ 0.90 [0.82–0.99]). LCZ696 was safe and well tolerated. These data support further clinical development of LCZ696, a novel, orally bioavailable, dual‐acting angiotensin receptor—NEP inhibitor (ARNi) for hypertension and heart failure.