Sacubitril

411.49

411.49

1592732-453-0

17ERJ0MKGI

DTXSID20164370

C152281

C09DX04

92.7

3.96

1.151±0.06 g/cm3(Predicted)

656.9±55.0 °C(Predicted)

351.1±31.5 °C

1.549

The most common adverse reactions (≥5%) are hypotension, hyperkalemia, cough, dizziness, and renal failure.

Sacubitril and it's metabolite, LBQ657 are highly bound to plasma protein (94-97%).

Used in combination with valsartan to reduce the risk of cardiovascular events in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction. It is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB.|FDA Label|Entresto is indicated in adult patients for treatment of symptomatic chronic heart failure with reduced ejection fraction.|Neparvis is indicated in adult patients for treatment of symptomatic chronic heart failure with reduced ejection fraction.|Treatment of heart failure|Prevention of heart failure

n a 7-day valsartan-controlled study in patients with reduced ejection fraction (HFrEF), administration of sacubitril + valsartan (Entresto) resulted in a significant non-sustained increase in natriuresis, increased urine cGMP, and decreased plasma MR-proANP and NT-proBNP compared to valsartan. In a 21-day study in HFrEF patients, it significantly increased urine ANP and cGMP and plasma cGMP, and decreased plasma NT-proBNP, aldosterone and endothelin-1. In clinical studies, this combination had no effect on QTc interval.

Peak plasma concentrations of sacubitril and it's metabolite, LBQ657 are reached in 0.5 hours and 2 hours respectively. Food does not clinically affect the systemic exposure of sacubitril or LBQ657. The oral bioavailability of sacubitril is >60%. It should be noted that the valsartan found in this combination is more bioavailable than other market available valsartan.|52% to 68% of sacubitril (primarily as the active metabolite LBQ657) is excreted in urine. 37% to 48% of sacubitril (primarily as LBQ657) is excreted in feces|103 L

Sacubitril is metabolized to LBQ657 by esterases. A low concentration (<10%) of a hydroxyl metabolite has been identified in plasma.

The half life of sacubitril is 1.1 to 3.6 hours, and the half life of it's metabolite LBQ657 is 9.9 to 11.1 hours.

Sacubitril's active metabolite, LBQ657 inhibits neprilysin, a neutral endopeptidase that would typically cleave natiuretic peptides, which includes: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and c-type natriuretic peptide (CNP). ANP and BNP are released under atrial and ventricle stress, which activate downstream receptors leading to vasodilation, natriuresis and diuresis. Under normal conditions, neprilysin breaks down other vasodilating peptides and also vasoconstrictors such as angiotensin I and II, endothelin-1 and peptide amyloid beta-protein. Therefore, the inhibition of neprilysin leads to reduced breakdown and increased concentration of endogenous natriuretic peptides in addition to increased levels of vasoconstricting hormones such as angiotensin II. (However, when combined with valsartan, would result in blocking of angiotensin II to its receptor, preventing the vasoconstrictive effects and resulting in a decrease in vascular resistance and blood pressure.) Cardiovascular and renal effects of sacubitril is a result of the increased levels of peptides that are normally degraded by neprilysin.

(2R,4S)-5-(biphenyl-4-yl)-4-((3-carboxypropionyl)amino)-2-methylpentanoic acid ethyl ester

Human drugs -> Entresto -> EMA Drug Category|Angiotensin II antagonists, other combinations, Agents acting on the renin-angiotensin system -> Human pharmacotherapeutic group|Human drugs -> Neparvis -> EMA Drug Category|Agents acting on the renin-angiotensin system -> Human pharmacotherapeutic group|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients