Pharmacology of Vericiguat

Vericiguat is a stimulator of soluble guanylate cyclase (sGC),it is used to reduce the risk of cardiovascular death and hospitalization for heart failure following a prior hospitalization for heart failure or need for outpatient intravenous diuretics, in adults with symptomatic chronic heart failure and an ejection fraction of less than 45%.

Pharmacology

Mechanism of Action

Vericiguat is a stimulator of soluble guanylate cyclase (sGC), an important enzyme in the nitric oxide (NO) signaling pathway. When NO binds to sGC, the enzyme catalyzes the synthesis of intracellular cyclic guanosine monophosphate (cGMP), a second messenger that plays a role in the regulation of vascular tone, cardiac contractility, and cardiac remodeling. Heart failure is associated with impaired synthesis of NO and decreased activity of sGC, which may contribute to myocardial and vascular dysfunction. By directly stimulating sGC, independently of and synergistically with NO, vericiguat augments levels of intracellular cGMP, leading to smooth muscle relaxation and vasodilation.

Absorption

Bioavailability: 93% when taken with food

Peak plasma time: 4 hr (with food)

Peak plasma concentration: 350 mcg/L

AUC: 6680 mcg⋅h/L

Steady-state achieved after ~6 days

Effect of food

With high-fat, high-calorie meal

Peak plasma time: 1 hr (fasting); 4 hr (fed)

Peak plasma concentration: Increased by 41%

AUC: Increased by 44%

Distribution

Vd: 44 L (healthy volunteers)

Protein bound: ~98%

Metabolism

Primarily undergoes glucuronidation by UGT1A9 and to a lesser extent by UGT1A1 to form an inactive N-glucuronide metabolite

CYP-mediated metabolism is a minor clearance pathway (<5%)

Elimination

Half-life: 30 hr (patients with HF)

Clearance: 1.6 L/hr (healthy volunteers)

Excretion, healthy volunteers

Urine: ~53% (primarily as inactive metabolite)

Feces: 45% (primarily as unchanged drug