Pharmacokinetics and Pharmacodynamics of LCZ696, a Novel Dual‐Acting Angiotensin Receptor—Neprilysin Inhibitor (ARNi)

  title={Pharmacokinetics and Pharmacodynamics of LCZ696, a Novel Dual‐Acting Angiotensin Receptor—Neprilysin Inhibitor (ARNi)},
  author={Jessie Gu and Adele No{\`e} and Priya Chandra and Suliman I. Al-Fayoumi and Monica Ligueros‐Saylan and Ramesh Sarangapani and Suzanne Maahs and Gary Michael Ksander and Dean F. Rigel and Arco Y. Jeng and Tsu-han Lin and Weiyi Zheng and William P. Dole},
  journal={The Journal of Clinical Pharmacology},
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… 

Safety, Pharmacokinetics, and Pharmacodynamics of TD‐0714, a Novel Potent Neprilysin Inhibitor in Healthy Adult and Elderly Subjects

The TD‐0714 PK and PD profiles support further clinical development of TD‐714 and suggest the potential for once‐daily administration and predictable exposure in patients with cardiorenal diseases regardless of their renal function.

Efficacy and Safety of LCZ696, a First-in-Class Angiotensin Receptor Neprilysin Inhibitor, in Asian Patients With Hypertension: A Randomized, Double-Blind, Placebo-Controlled Study

In conclusion, LCZ696 is effective for the treatment of hypertension in Asian population and, in general, is safe and well tolerated.

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

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, comparable to that observed in the pivotal Phase III study.

Assessment of Drug–Drug Interaction Potential Between Atorvastatin and LCZ696, A Novel Angiotensin Receptor Neprilysin Inhibitor, in Healthy Chinese Male Subjects

While atorvastatin had no significant impact on the pharmacokinetics of LCZ696 analytes upon co-administration, the Cmax of atorVastatin and its metabolites increased twofold, with a marginal increase in AUC.

Effects of age and sex on the pharmacokinetics of LCZ696, an angiotensin receptor neprilysin inhibitor

All pharmacokinetic parameters ofLCZ696 analytes (LBQ657 and valsartan) were similar between male and female subjects, indicating no effect on the pharmacokinetics of LCZ696 analyzetes based on sex.

LCZ696, a First‐in‐Class Angiotensin Receptor‐Neprilysin Inhibitor: The First Clinical Experience in Patients With Severe Hypertension

The LCZ696‐based regimen was generally well‐tolerated and could present a treatment option for severe hypertension in Asian patients especially in reducing SBP and pulse pressure.

Pharmacokinetic drug–drug interaction assessment between LCZ696, an angiotensin receptor neprilysin inhibitor, and hydrochlorothiazide, amlodipine, or carvedilol

LCZ696, HCTZ, amlodipine, and carvedilol were safe and well tolerated when given alone or concomitantly in the investigated studies.

Focus on the Novel Cardiovascular Drug LZC696: from Evidence to Clinical Consideration

Accumulating evidence suggests its potential use in heart failure with preserved ejection fraction (HFpEF), chronic kidney disease (CKD), post-myocardium infarction (post-MI) and stroke, and some special issues should be considered before its implementation in clinical practice.

LCZ696: The Next Step in Improving RAS Inhibition?

  • A. Gradman
  • Medicine
    Current Hypertension Reports
  • 2015
LCZ696 is a single molecule which combines the angiotensin receptor blocker valsartan with the neprilysn inhibitor sacubitril (AHU377). In the recently published PARADIGM-HF trial, LCZ696 proved



Lack of pharmacokinetic interactions of aliskiren, a novel direct renin inhibitor for the treatment of hypertension, with the antihypertensives amlodipine, valsartan, hydrochlorothiazide (HCTZ) and ramipril in healthy volunteers

Aliskiren shows no clinically relevant pharmacokinetic interactions and is generally well tolerated when administered in combination with amlodipine, valsartan, HCTZ or ramipril.

Pharmacokinetics and pharmacodynamic effects of the angiotensin II antagonist valsartan at steady state in healthy, normotensive subjects

Valsartan is well tolerated and is devoid of effects on water, electrolyte and uric acid excretion at 200 mg per day in healthy normotensive volunteers, and indirect evidence of AT1 blockade by valsartans is demonstrated.

CGS 35601 and its Orally Active Prodrug CGS 37808 as Triple Inhibitors of Endothelin-converting Enzyme-1, Neutral Endopeptidase 24.11, and Angiotensin-converting Enzyme

By suppressing the biosyntheses of endothelin-1 and angiotensin II, two potent vasoconstrictors, while simultaneously potentiating the circulating levels of ANP, a vasorelaxant and diuretic, CGS 35601 and CGS 37808 may represent novel agents for the treatment of cardiovascular and renal diseases.

Candoxatril, an orally active neutral endopeptidase inhibitor, raises plasma atrial natriuretic factor and is natriuretic in essential hypertension

The drug caused a rise in basal ANF levels at all doses, but natriuresis was only seen with the highest dose used, and oral inhibitors of ANF degradation may have therapeutic potential in cardiovascular disorders.

Chronic inhibition of endopeptidase 24.11 in essential hypertension: evidence for enhanced atrial natriuretic peptide and angiotensin II

Candoxatril augments the effects of ANF and lowers blood pressure in patients with hypertension, however, the antihypertensive effects may be offset by increased angiotensin-aldosterone and sympathetic nervous system activity.

The angiotensin receptor antagonist valsartan: a review of the literature with a focus on clinical trials

In diabetic patients with microalbuminuria, valsartan has been shown to have benefits beyond those attributable to blood pressure lowering alone, and was shown to reduce the risk of developing new-onset diabetes in hypertensive patients at high risk of cardiac events compared with calcium antagonist treatment.

Inhibition of endopeptidase EC 24.11 in humans. Renal and endocrine effects.

Therapeutic trials of such inhibitors are now indicated for hypertension or heart failure together with further studies to clarify the underlying mechanisms of action.

Pharmacokinetics and pharmacodynamics of the vasopeptidase inhibitor, omapatrilat in healthy subjects.

The pharmacokinetic and pharmacodynamic effects of omapatrilat are consistent with once-daily dosing, and it is concluded that omap atrilat was generally well tolerated.

Effects of omapatrilat on pharmacodynamic biomarkers of neutral endopeptidase and angiotensin-converting enzyme activity in humans

The pharmacodynamic effects of the vasopeptidase inhibitor omapatrilat on biomarkers of NEP and ACE activity in humans are outlined.