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Usage of Sacubitril Calcium Salt

Sacubitril calcium salt (CAS No.: 1369773-39-6) is a prodrug and a key component of the heart failure medication LCZ696 (brand name: Entresto®), which combines sacubitril with the angiotensin receptor blocker (ARB) valsartan. Its primary mechanism of action involves inhibiting the enzyme neprilysin (neutral endopeptidase, NEP), thereby preventing the breakdown of natriuretic peptides, bradykinin, and other vasoactive peptides. This leads to enhanced vasodilation, natriuresis, and diuresis, ultimately reducing cardiovascular strain in patients with heart failure.

1. Therapeutic Indications

Sacubitril calcium salt is indicated for the treatment of:

• Heart failure with reduced ejection fraction (HFrEF): To reduce the risk of cardiovascular death and hospitalization for heart failure.
• Chronic heart failure: As part of a comprehensive treatment regimen to improve symptoms and outcomes.

2. Dosage and Administration

• Formulation: Sacubitril calcium salt is administered orally as part of a fixed-dose combination tablet with valsartan (LCZ696).
• Dosing: The recommended starting dose is typically 49 mg sacubitril/51 mg valsartan twice daily, which may be titrated up to 97 mg sacubitril/103 mg valsartan twice daily based on patient tolerance and clinical response.
• Adjustment for Renal or Hepatic Impairment: Dose adjustments may be necessary in patients with severe renal or hepatic dysfunction.

3. Mechanism of Action

• Prodrug Activation: Sacubitril is rapidly metabolized by esterases to its active form, LBQ657, which potently inhibits neprilysin (IC₅₀ ≈ 5 nM).
• Synergistic Effects: By inhibiting neprilysin, sacubitril increases the levels of natriuretic peptides, while valsartan blocks the angiotensin II type 1 receptor (AT₁), reducing vasoconstriction and aldosterone secretion. This dual mechanism provides superior efficacy compared to monotherapy with an ACE inhibitor or ARB alone.

4. Pharmacokinetics

• Absorption: Bioavailability is approximately 60–80% when administered with food.
• Distribution: Widely distributed in tissues, with a volume of distribution of approximately 75–100 L.
• Metabolism: Sacubitril is rapidly converted to LBQ657 via hepatic esterases. Valsartan undergoes minimal metabolism and is primarily eliminated unchanged in the feces (≈93%) and urine (≈40%).
• Elimination: The half-life of LBQ657 is approximately 11–15 hours, allowing for twice-daily dosing.

5. Contraindications and Precautions

• Contraindications:
  • History of angioedema related to prior ACE inhibitor or ARB therapy.
  • Concomitant use with aliskiren in patients with diabetes mellitus.
• Precautions:
  • Hypotension: Risk of symptomatic hypotension, especially in patients with volume depletion or severe heart failure.
  • Renal Function: Monitor renal function and serum potassium levels, as changes may occur due to altered hemodynamics.
  • Pregnancy: Avoid use during pregnancy due to potential fetal toxicity (Category D).

6. Adverse Effects

Common adverse effects include:

• Hypotension
• Hyperkalemia
• Renal impairment
• Cough (less frequent than with ACE inhibitors)
• Angioedema (rare)

7. Drug Interactions

• Avoid Concomitant Use: With aliskiren in patients with diabetes or renal impairment.
• Potentiates Effects: Of other antihypertensive agents, diuretics, or potassium-sparing agents (monitor potassium levels).

8. Clinical Efficacy

• PARADIGM-HF Trial: LCZ696 demonstrated a 20% reduction in the risk of cardiovascular death and a 21% reduction in heart failure hospitalizations compared to enalapril, an ACE inhibitor.
• Long-Term Benefits: Improved quality of life, reduced symptoms, and slowed disease progression in patients with HFrEF.

9. Regulatory Status

• Approvals: Approved by the FDA (2015), EMA (2015), and other regulatory agencies for the treatment of HFrEF.

10. Research and Development

• Ongoing studies are exploring its use in:
  • Heart failure with preserved ejection fraction (HFpEF).
  • Acute decompensated heart failure.
  • Combination therapies with other cardiovascular agents.