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      Pharmacodynamic and Pharmacokinetic Profiles of Sacubitril/Valsartan (LCZ696) in Patients with Heart Failure and Reduced Ejection Fraction

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          Concomitant renin–angiotensin–aldosterone system blockade and natriuretic peptide system enhancement may provide unique therapeutic benefits to patients with heart failure and reduced ejection fraction ( HFr EF). This study assessed the pharmacodynamics and pharmacokinetics of LCZ696 in patients with HFr EF.


          This was an open‐label, noncontrolled single‐sequence study. After a 24‐h run‐in period, patients (n = 30) with HFr EF ( EF ≤ 40%; NYHA class IIIV) received LCZ696 100 mg twice daily (bid) for 7 days and 200 mg bid for 14 days, along with standard treatment for heart failure ( HF) (except angiotensin‐converting enzyme inhibitors [ ACEIs] or angiotensin receptor blockers [ ARBs]).


          On Day 21, significant increases were observed in the plasma biomarkers indicative of neprilysin and RAAS inhibition (ratio‐to‐baseline: cyclic guanosine monophosphate [ cGMP], 1.38; renin concentration and activity, 3.50 and 2.27, respectively; all, <  0.05). Plasma NT‐pro BNP levels significantly decreased at all the time points on Days 7 and 21; plasma aldosterone and endothelin‐1 levels significantly decreased on Day 21 (all, <  0.05). Following administration of LCZ696, the C max of sacubitril (neprilysin inhibitor prodrug), LBQ657 (active neprilysin inhibitor), and valsartan were reached within 0.5, 2.5, and 2 h. Between 100‐ and 200‐mg doses, the C max and AUC 0–12 h for sacubitril and LBQ657 were approximately dose‐proportional while that of valsartan was less than dose‐proportional.


          Treatment with LCZ696 for 21 days was well tolerated and resulted in plasma biomarker changes indicative of neprilysin and RAAS inhibition in patients with HF. The pharmacokinetic exposure of the LCZ696 analytes in patients with HF observed in this study is comparable to that observed in the pivotal Phase III study.

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          Most cited references 13

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          Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions.

          Natriuretic peptides are a family of structurally related but genetically distinct hormones/paracrine factors that regulate blood volume, blood pressure, ventricular hypertrophy, pulmonary hypertension, fat metabolism, and long bone growth. The mammalian members are atrial natriuretic peptide, B-type natriuretic peptide, C-type natriuretic peptide, and possibly osteocrin/musclin. Three single membrane-spanning natriuretic peptide receptors (NPRs) have been identified. Two, NPR-A/GC-A/NPR1 and NPR-B/GC-B/NPR2, are transmembrane guanylyl cyclases, enzymes that catalyze the synthesis of cGMP. One, NPR-C/NPR3, lacks intrinsic enzymatic activity and controls the local concentrations of natriuretic peptides through constitutive receptor-mediated internalization and degradation. Single allele-inactivating mutations in the promoter of human NPR-A are associated with hypertension and heart failure, whereas homozygous inactivating mutations in human NPR-B cause a form of short-limbed dwarfism known as acromesomelic dysplasia type Maroteaux. The physiological effects of natriuretic peptides are elicited through three classes of cGMP binding proteins: cGMP-dependent protein kinases, cGMP-regulated phosphodiesterases, and cyclic nucleotide-gated ion channels. In this comprehensive review, the structure, function, regulation, and biological consequences of natriuretic peptides and their associated signaling proteins are described.
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            Angiotensin receptor neprilysin inhibitor LCZ696 attenuates cardiac remodeling and dysfunction after myocardial infarction by reducing cardiac fibrosis and hypertrophy.

            Angiotensin receptor neprilysin inhibitors (ARNi), beyond blocking angiotensin II signaling, augment natriuretic peptides by inhibiting their breakdown by neprilysin. The myocardial effects of ARNi have been little studied until recently. We hypothesized that LCZ696 attenuates left ventricular (LV) remodeling after experimental myocardial infarction (MI), and that this may be contributed to by inhibition of hypertrophy and fibrosis in cardiac cells.
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              Neutral endopeptidase inhibition and the natriuretic peptide system: an evolving strategy in cardiovascular therapeutics.

              Hypertension and heart failure (HF) are common diseases that, despite advances in medical therapy, continue to be associated with high morbidity and mortality. Therefore, innovative therapeutic strategies are needed. Inhibition of the neutral endopeptidase (NEPinh) had been investigated as a potential novel therapeutic approach because of its ability to increase the plasma concentrations of the natriuretic peptides (NPs). Indeed, the NPs have potent natriuretic and vasodilator properties, inhibit the activity of the renin-angiotensin-aldosterone system, lower sympathetic drive, and have antiproliferative and antihypertrophic effects. Such potentially beneficial effects can be theoretically achieved by the use of NEPinh. However, studies have shown that NEPinh alone does not result in clinically meaningful blood pressure-lowering actions. More recently, NEPinh has been used in combination with other cardiovascular agents, such as angiotensin-converting enzyme inhibitors, and antagonists of the angiotensin receptor. Another future possible combination would be the use of NEPinh with NPs or their newly developed chimeric peptides. This review summarizes the current knowledge of the use and effects of NEPinh alone or in combination with other therapeutic agents for the treatment of human cardiovascular disease such as HF and hypertension.

                Author and article information

                Cardiovasc Ther
                Cardiovasc Ther
                Cardiovascular Therapeutics
                John Wiley and Sons Inc. (Hoboken )
                06 July 2016
                August 2016
                : 34
                : 4 ( doiID: 10.1111/cdr.2016.34.issue-4 )
                : 191-198
                [ 1 ] Center of Applied Clinical PharmacologyPeoples Friendship University of Russia MoscowRussia
                [ 2 ] Translational MedicineNovartis Pharma AG BaselSwitzerland
                [ 3 ] Drug Metabolism and Pharmacokinetics, Clinical Pharmacokinetic/PharmacodynamicsNovartis Institute for Biomedical Research East Hanover NJUSA
                [ 4 ] Clinical Development and Medical AffairsNovartis Pharmaceutical Corporation East Hanover NJUSA
                [ 5 ] Biostatistical SciencesNovartis Healthcare Private Limited HyderabadIndia
                [ 6 ]Present address: Genentech, Inc.Clinical Pharmacology South San Francisco CAUSA
                Author notes
                [* ] Correspondence

                Z. Kobalava, M.D., Ph.D., Department of Cardiology and Clinical Pharmacology, Hospital 64, Peoples Friendship University of Russia, Vavilova Street 61, Moscow 117292, Russia.

                Tel.: +7499‐134‐6591;

                Fax: +7499‐134‐83‐06;

                E‐mail: zkobalava@

                © 2016 The Authors Cardiovascular Therapeutics Published by John Wiley & Sons Ltd

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                Page count
                Figures: 3, Tables: 3, Pages: 8, Words: 5163
                Funded by: Novartis Pharma AG, Basel, Switzerland
                Original Research Article
                Original Research Articles
                Custom metadata
                August 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.7 mode:remove_FC converted:14.11.2016


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