Indications
Vericiguat is prescribed for adult patients experiencing symptomatic, chronic heart failure with an ejection fraction of less than 45%. It serves to mitigate the risk of cardiovascular death and reduce the necessity for hospitalization due to heart failure, especially following an acute episode that required either hospitalization or outpatient intravenous diuretics.
Pharmacodynamics
The pharmacodynamic action of vericiguat involves the stimulation of intracellular cyclic guanosine monophosphate (cGMP) production, which promotes relaxation of vascular smooth muscles and subsequent vasodilation. Vericiguat features a substantial half-life of approximately 30 hours, permitting a convenient once-daily dosing regimen. It is critical to note that animal studies indicate potential embryo-fetal toxicity; exposure during pregnancy has been linked to defects in major vessel and heart formation, alongside instances of spontaneous abortions. Therefore, pregnancy should be ruled out before commencing therapy, and effective contraception is advised during treatment and for one month afterward.
Absorption
When administered orally at a dosage of 10 mg daily, vericiguat achieves an average steady-state maximum concentration (Cmax) of 350 mcg/L and area under the curve (AUC) of 6,680 mcg·h/L, with a time to peak concentration (Tmax) of approximately one hour. Oral bioavailability of vericiguat is estimated to be about 93%, especially when taken with food. Co-administration with meals not only enhances this bioavailability but also increases Tmax to approximately four hours and raises both Cmax and AUC by 41% and 44%, respectively, thereby reducing pharmacokinetic variability.
Metabolism
The metabolism of vericiguat predominantly occurs through phase II conjugation reactions. Oxidative metabolism mediated by cytochrome P450 enzymes plays a minor role, contributing to less than 5% of its overall biotransformation. UGT1A9 and, to a lesser extent, UGT1A1 are responsible for the formation of its primary inactive metabolite, vericiguat N-glucuronide (M1). Additional metabolites have been identified, including a debenzylated compound and an M15 metabolite potentially arising from oxidative metabolism, though these are not thoroughly characterized.
Mechanism of Action
In heart failure, both morphological and physiological changes occur, notably including impaired nitric oxide (NO) synthesis and reduced soluble guanylate cyclase (sGC) activity. Under normal conditions, NO activates sGC, leading to the production of intracellular cyclic guanosine monophosphate (cGMP), a critical second messenger responsible for regulating vascular tone, cardiac contractility, and remodeling. Disruptions in this pathway are believed to contribute to the myocardial and vascular dysfunctions associated with heart failure, making it a key target for therapeutic intervention. Vericiguat serves this purpose by directly stimulating sGC through binding to its beta-subunit, thereby circumventing the need for NO-mediated activation. This interaction enhances the production of intracellular cGMP, promoting vascular smooth muscle relaxation and vasodilation.
