Sacubitril / Valsartan

Mechanism

Pharmacological Class and Group

Dual neurohumoral modulator belonging to the class of Neprilysin and Angiotensin Receptor Inhibitors (ARNI). It consists of an anionic crystalline molecular complex containing sacubitril (neprilysin inhibitor prodrug) and valsartan (AT₁ receptor antagonist) in a stoichiometric ratio of 1:1.

Mechanism of Action

In heart failure, the myocardium suffers wall stress, activating the RAAS and the sympathetic nervous system, in addition to promoting the synthesis of natriuretic peptides (ANP, BNP). Neprilysin (neutral endopeptidase 24.11) is a membrane-bound enzyme expressed primarily in the kidney and lung that degrades natriuretic peptides and other vasoactive signaling molecules.

Dual Synergistic Mechanism of the ARNI

1. Inhibition of Neprilysin by Sacubitrilat (LBQ657): Sacubitril is hydrolyzed by tissue esterases to form LBQ657, a potent inhibitor of neprilysin. This blockade prevents the enzymatic degradation of endogenous natriuretic peptides (Atrial Natriuretic Peptide [ANP] and Brain Natriuretic Peptide [BNP]):

↑ [ANP / BNP] NPR-A Receptor Stimulation ↑ cGMP Vasodilatation, Natriuresis and Anti-fibrosis

2. AT₁ Receptor Antagonism by Valsartan: Sacubitril also prevents the degradation of Angiotensin II by neprilysin. If neprilysin were inhibited in isolation, the increase in Angiotensin II would counteract the benefits of natriuretic peptides. Therefore, the mandatory inclusion of valsartan selectively blocks the destructive effects of Angiotensin II on the AT₁ receptor:

Valsartan AT Receptor₁ Blockade of vasoconstriction and secondary myocardial remodeling

3. Net Clinical Effect: Balanced modulation that directly improves long-term myocardial function, drastically reducing myocyte apoptosis and preventing the synthesis of pathological interstitial collagen (anti-cardiac fibrosis).

Pharmacokinetics

High Resolution Pharmacokinetics

• Absorption and Bioavailability: After oral administration, the complex quickly dissociates into sacubitril and valsartan. Sacubitril reaches its maximum concentration (C_max) in 1.5 hours, while valsartan reaches it in 2 hours. The bioavailability of the valsartan fraction in the complex is approximately 50% higher than that of the conventional valsartan monotherapy formulation.
• Distribution: Both sacubitriloat (LBQ657) and valsartan are highly bound to plasma proteins (97% - 98%). Its apparent volume of distribution is relatively low (75 L to 100 L).
• Metabolism: Sacubitril is rapidly biotransformed by hepatic esterases to sacubitriloat (LBQ657), which does not undergo further extensive oxidative metabolism. Valsartan is eliminated largely without alterations through the bile route.
• Excretion: Sacubitriloat is eliminated predominantly by renal excretion (52% to 68%) and to a lesser extent by the fecal route (37% to 48%). Valsartan is primarily eliminated via the fecal/biliary route.
• Half-life (t_1/2): The terminal elimination half-life is approximately 11.5 hours for sacubitriloat and 12 hours for valsartan, requiring a strict every 12-hour dosing schedule.

Indicators and dose

Clinical Indications and Uses

• Heart Failure with Reduced Ejection Fraction (HFrEF): First-line treatment in patients with NYHA functional class II-IV, preferably replacing previous therapy with ACEIs or ARBs to reduce cardiovascular mortality and the frequency of hospitalizations (according to results of the pivotal PARADIGM-HF clinical trial).
• Heart Failure with Preserved or Slightly Reduced Ejection Fraction (HFpEF / HFrEF): Indicated to reduce hospitalizations in selected patients, especially those with ejection fraction below normal limit values.

Dosage and Clinical Adjustment

The dose of sacubitril/valsartan is usually expressed according to the sum of the mass of both active components (24/26 mg sacubitril/valsartan, 49/51 mg and 97/103 mg, equivalent to the nominal doses of 50 mg, 100 mg and 200 mg free base, respectively):

• Standard Initial Dose: 49/51 mg (100 mg nominal) twice daily orally.
• Reduced Initial Dose (24/26 mg twice a day): Mandatory in patients who previously received low doses of ACEI or ARA-II, in those over 75 years of age, in patients with eGFR less than 30 mL/min/1.73 m² or with moderate liver failure (Child-Pugh Class B).
• Target Maintenance Dose: 97/103 mg (200 mg nominal) twice daily. Double the dose every 2 to 4 weeks depending on hemodynamic tolerance and serum potassium.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Concomitant use with an ACEI: The simultaneous use of sacubitril/valsartan and an ACEI critically increases the probability of the appearance of angioedema. A strict washout period of 36 hours is required between the last dose of ACEI and the first intake of ARNI.
• History of hereditary, idiopathic or previous angioedema induced by ACEI/ARB.
• Pregnancy: Absolute contraindication due to direct toxicity to the fetal renal axis.
• Severe liver failure (Child-Pugh Class C).

Relative Contraindications

• Moderate to severe renal impairment with eGFR less than 30 mL/min/1.73 m² (requires a reduction in the starting dose).
• Active hyperkalemia of moderate to severe range (K⁺ > 5.5 mEq/L).
• Bilateral renal artery stenosis.

Adverse Effects and Toxicity

• Symptomatic Arterial Hypotension: It is the most frequent dose-limiting side effect, due to the powerful synergistic vasodilator effect of the drug. It usually requires slower titration or adjustment of the background diuretic treatment.
• Hyperkalemia: Observed in predisposed patients; Its frequency is slightly lower than with conventional enalapril.
• Acute Kidney Failure: Generally reversible with adjustment of the associated diuretic.

Class Alert: Mandatory 36 Hour Washing Rule

Neprilysin and ACE are the two main enzymes responsible for the degradation and metabolic clearance of circulating bradycidin. The simultaneous inhibition of both pathways (ARNI + ACEI) causes a massive accumulation of bradycidin, triggering the incidence of severe angioedema with danger of asphyxiation:

Last ACEI dose Wait strictly 36 hours Start Sacubitrile/Valsartan

This rule does not apply when switching from an ARB to sacubitril/valsartan (where the ARNI can be started at the next scheduled dosing interval), since ARBs do not directly inhibit the enzymatic degradation of bradycidin.

Relevant Drug Interactions

• NSAIDs: May further deteriorate kidney function acutely in patients with decompensated heart failure.
• Potassium and Potassium-Sparing Diuretics: Hyperkalemia synergism.
• Lithium: Increased risk of lithium toxicity as its urinary fractional clearance is competitively reduced.