title: Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi).
abstract: 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-infinity) 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.
authors.affiliation: Cardiovascular and Metabolism Translational Medicine, Novartis Institutes for BioMedical Research, Inc, 220 Mass Avenue, Cambridge, MA 02139, USA. jessie.gu@novartis.com
authors.forename: Jessie
authors.initials: J
authors.lastname: Gu
authors.forename: Adele
authors.initials: A
authors.lastname: Noe
authors.forename: Priya
authors.initials: P
authors.lastname: Chandra
authors.forename: Suliman
authors.initials: S
authors.lastname: Al-Fayoumi
authors.forename: Monica
authors.initials: M
authors.lastname: Ligueros-Saylan
authors.forename: Ramesh
authors.initials: R
authors.lastname: Sarangapani
authors.forename: Suzanne
authors.initials: S
authors.lastname: Maahs
authors.forename: Gary
authors.initials: G
authors.lastname: Ksander
authors.forename: Dean F
authors.initials: DF
authors.lastname: Rigel
authors.forename: Arco Y
authors.initials: AY
authors.lastname: Jeng
authors.forename: Tsu-Han
authors.initials: TH
authors.lastname: Lin
authors.forename: Weiyi
authors.initials: W
authors.lastname: Zheng
authors.forename: William P
authors.initials: WP
authors.lastname: Dole
mesh_terms: D000293:Adolescent; D000328:Adult; D000613:Aminobutyrates / Q000493:pharmacokinetics*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000493:pharmacokinetics*; D015331:Cohort Studies; D018592:Cross-Over Studies; D004285:Dogs; D004311:Double-Blind Method; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D013777:Tetrazoles / Q000493:pharmacokinetics*; D000068756:Valsartan; D055815:Young Adult
chemical_list: D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D004338:Drug Combinations; C000609743:LBQ657; D013777:Tetrazoles; D000068756:Valsartan; D015260:Neprilysin; C549068:sacubitril and valsartan sodium hydrate drug combination