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- Title
Vericiguat, a novel sGC stimulator: Mechanism of action, clinical, and translational science.
- Authors
Trujillo, Maria E.; Ayalasomayajula, Surya; Blaustein, Robert O.; Gheyas, Ferdous
- Abstract
Vericiguat, a novel soluble guanylate cyclase (sGC) stimulator, is approved for the treatment of heart failure (HF) with reduced ejection fraction (HFrEF). Decreased nitric oxide (NO) availability, sGC desensitization to NO, sGC deficiency, and reduced cyclic guanosine monophosphate (cGMP) signaling are potential contributing factors for HF disease progression. Vericiguat works via stimulation of sGC in the critical NO‐sGC‐cGMP pathway. Vericiguat is primarily metabolized by glucuronidation via uridine diphosphate‐glucuronosyltransferase (UGT) isoforms UGT1A1 and UGT1A9. Urinary excretion and renal clearance of vericiguat are low. No intrinsic factor had a clinically relevant effect on vericiguat exposure. Vericiguat has low drug–drug interaction potential with no clinically relevant pharmacokinetic or pharmacodynamic interactions observed with warfarin, digoxin, aspirin, or sacubitril/valsartan. The global phase III study VICTORIA included patients with HFrEF who had a recent HF hospitalization or intravenous diuretic treatment for HF. Treatment with vericiguat on top of standard of care resulted in a 10% relative reduction in the primary composite outcome of death from cardiovascular causes or first hospitalization for HF. Vericiguat was well‐tolerated with low incidence of symptomatic hypotension and syncope compared to placebo. Given its positive benefit–risk profile, vericiguat is an important option for high‐risk patients with HFrEF who are already on guideline‐directed medical therapy and had recent worsening of HF. Future efforts to develop additional effective therapies are needed to further reduce morbidity and mortality in patients with HF. Clinical and Translational Card for VericiguatMechanism of action: sGC stimulator.Indication(s): In the US, vericiguat is indicated for the treatment of adults with symptomatic chronic HF and EF less than 45% following a hospitalization for HF or need for outpatient IV diuretics.Dosage and administration: A starting dose of 2.5 mg is administered orally once daily with food. The dose is then doubled approximately every 2 weeks to reach the target maintenance dose of 10 mg once daily with food, as tolerated by the patient.Major metabolic pathway: Vericiguat primarily undergoes glucuronidation by UGT1A9 and to a lesser extent by UGT1A1. CYP‐mediated metabolism is a minor clearance pathway (<5%).Key PK characteristics: The time to maximum concentration of vericiguat is approximately 4 hours when taken with food; the half‐life is 30 hours in patients with HFrEF. The peak serum concentrations (Cmax) and % coefficient of variation (CV) for vericiguat 2.5 mg, 5 mg, and 10 mg are 120 μg/L (29%), 201 μg/L (29%), and 350 μg/L (29%), respectively. The areas under the curve (AUC) and % CV for vericiguat 2.5 mg, 5 mg, and 10 mg are 2300 μg×h/L (33.9%), 3850 μg×h/L (33.9%), and 6680 μg×h/L (33.9%), respectively.
- Subjects
CYCLIC guanylic acid; DRUG dosage; DRUG interactions; GUANYLATE cyclase; HEART failure
- Publication
CTS: Clinical & Translational Science, 2023, Vol 16, Issue 12, p2458
- ISSN
1752-8054
- Publication type
Article
- DOI
10.1111/cts.13677