Vericiguat

Vericiguat is a Vasodilator and Soluble guanylate cyclase (sGC) stimulator that is used in the treatment of heart failure with reduced ejection fraction (HFrEF).

The absolute bioavailability of orally-administered vericiguat is approximately 93% when taken with food. In healthy subjects, the steady-state volume of distribution of vericiguat is approximately 44 liters. Vericiguat is primarily metabolized via phase II conjugation reactions, with CYP-mediated oxidative metabolism comprising a small (<5%) portion of its overall biotransformation. Following the oral administration of radiolabeled vericiguat, approximately 53% of the administered radioactivity was recovered in the urine and 45% in the feces. While virtually the entire portion recovered in the feces comprised unchanged vericiguat

The common side effects are anemia, Low blood pressure, pale skin, unusual tiredness, feeling light-headed or short of breath, cold hands, and feet, a light-headed feeling, etc.

Vericiguat is available in the dosage forms such as tablets.

Vericiguat is available in China, Australia, Japan, India, USA, UK

Vericiguat directly stimulates sGC by binding to a target site on its beta-subunit, bypassing the need for NO-mediated activation, and in doing so, causes an increase in the production of intracellular cGMP that results in vascular smooth muscle relaxation and vasodilation.

Vericiguat restores the cyclic guanosine monophosphate under low nitric oxide conditions and oxidative stress.

The half life of Vericiguat was within 30 hours

The Tmax was about 1 hour and Cmax was about 350 mcg/L

Vericiguat is available in the form of tablets.

For Tablets:

Vericiguat tablets should be taken orally by mouth with or without water.

Vericiguat stimulates soluble guanylate cyclase that activates the cGMP pathway independent of nitric oxide involvement. It also sensitizes soluble guanylate cyclase to nitric oxide by stabilizing nitric oxide binding to the binding site.

Vericiguat is a Vasodilator/Soluble guanylate cyclase (sGC) stimulator that acts as an antihypertensive agent used to treat heart failure with reduced ejection fraction (HFrEF).

Vericiguat is approved for use in the following clinical indications

• Heart failure with a reduced ejection fraction

Indicated to decrease the risk of cardiovascular death and heart failure (HF) hospitalization following hospitalization for HF or the need for outpatient IV diuretics, in adults with symptomatic chronic HF and ejection fraction <45%

Initial: 2.5 mg taken orally four times a day.

Maintenance: Double dose ~Twice a week as tolerated to a target dose of 10 mg taken by mouth once a day.

The dosage and the duration of treatment should be as per the clinical judgment of the treating physician

Vericiguat is available in various dosage strengths of 2.5mg, 5 mg, and 10 mg.

Vericiguat is available in a dosage forms such as tablets.

Vericiguat should be used in the treatment of heart failure with reduced ejection fraction (HFrEF).

Heart failure: Choose plenty of fresh fruits and vegetables. They contain only small amounts of salt. Choose foods that are low in salts, such as fresh meats, poultry, fish, dry and fresh legumes, eggs, milk, and yogurt. Plain rice, pasta, and oatmeal are good low-sodium choices.

The dietary restriction should be individualized as per the patient's requirements.

Vericiguat may be contraindicated in the following

• Vericiguat should be avoided in patients taking long-acting nitrates, soluble guanylate cyclase stimulators, or phosphodiesterase type 5 (PDE-5) inhibitors concerning hypotension and syncope.
• Clinicians should also avoid using the drug in patients with severe anemia because of concerns of a decrease in hemoglobin level with vericiguat

The treating physician must closely monitor the patient and keep pharmacovigilance as follows.

Warnings

• Embryo-Fetal Toxicity

Based on data from animal reproduction studies, Vericiguat may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential of the potential risk to a fetus. Obtain a pregnancy test before the start of treatment. Advise females of reproductive potential to use effective contraception during treatment with Vericiguat and for at least one month after the final dose.

Alcohol consumption with Vericiguat may increase the risk of low blood pressure and cause adverse effects, such as dizziness, fainting, light-headedness, or headache.

• Data not available on the presence of vericiguat in human milk, effects on breastfed infants, or effects on milk production
• Vericiguat is present in the milk of lactating rats and Vericiguat or its metabolites are likely to present in human milk
• Owing to the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment

US FDA pregnancy category: Not assigned.

Risk summary: Based on animal data, this drug may cause fetal harm; no data is available on the use of this drug in pregnant women.

Take each dose of vericiguat at the same time each day with food. If the patient receives enteral nutrition (tube feeding), take vericiguat with feeding. Taking it on an empty stomach may lead to inadequate blood levels and reduced effectiveness of the medication.

The adverse reactions related to the molecule Vericiguat can be classified as

• Common Adverse effects:

Hemodynamic compromise, Dizziness, peripheral ischemia, dry mouth, asthenia, and somnolence.

• Less Common adverse effects:

Asymptomatic and symptomatic hypotension, burning, crawling, itching, numbness.

• Rare adverse effects:

Bradycardia, decompensated heart failure, cardiac arrest, and heart block.

The clinically relevant drug interactions of Vericiguat are briefly summarized here.

Other Soluble Guanylate Cyclase Stimulators.

• Vericiguat is contraindicated in patients with concomitant use of another soluble guanylate cyclase (GC)Stimulators
• PDE-5 Inhibitors concomitant use of Vericiguat with PDE-5 inhibitors is not recommended because of the potential for Hypotension.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

Limited data are available with regard to overdosage in human patients treated with Vericiguat, doses up to 10 mg have been studied. In a study of patients with preserved ejection fraction heart failure (left ventricular ejection fraction ≥45%), multiple doses of vericiguat 15 mg have been studied and were generally well tolerated. In the event of an overdose, hypotension may result. Symptomatic treatment should be provided. Vericiguat is unlikely to be removed by hemodialysis because of high protein binding.

Pharmacodynamics:

● The mean reduction in systolic blood pressure was approximately 1 to 2 mm Hg greater in patients who received vericiguat compared with placebo.

● Vericiguat demonstrated a dose-dependent reduction in NT-proBNP, a biomarker in heart failure, at 12 weeks compared to placebo when added to the standard of care. The estimated reduction from baseline NT-proBNP at week 32 was greater in patients who received vericiguat compared with placebo.

● Cardiac Electrophysiology

● There was no evidence of proarrhythmic risk in an in vitro assessment of vericiguat or its major N-glucuronide metabolite. No inhibition of cardiac ion channels (hERG, hNav1.5, or hKvLQT1/mink) was observed at substantial multiples of their unbound Cmax values at the recommended target dose of 10 mg.

● The integrated risk assessment of nonclinical and clinical data supports that administration of vericiguat 10 mg is not associated with clinically meaningful QTc prolongation.

Pharmacokinetics:

• Absorption

The absolute bioavailability of vericiguat is 93% when taken with food. Results were comparable when vericiguat was administered orally as a whole tablet or as a crushed tablet in water.

• Effects of Food

Administration of vericiguat 10 mg with a high-fat, high-calorie meal increases Tmax from about 1 hour (fasted) to about 4 hours (fed), reduces PK variability, and increases vericiguat AUC by 44% and Cmax by 41% compared with administration in the fasted state. Similar results were obtained when vericiguat was administered with a low-fat, low-calorie meal when compared to administration with a high-fat, high-calorie meal.

• Distribution

The mean steady-state volume of distribution of vericiguat is approximately 44 L in healthy subjects. Protein binding (primarily to serum albumin) of vericiguat is about 98%.

The half-life of vericiguat is 30 hours in patients with heart failure. Clearance in healthy subjects is 1.6 L/h.

• Metabolism

Vericiguat 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%).

• Excretion

Following oral administration of radiolabeled vericiguat to healthy subjects, approximately 53% of the dose was excreted in urine (primarily as an inactive metabolite) and 45% in feces (primarily as an unchanged drug).

It gets excreted Via faeces (approx 53%); urine (approx 40%). Elimination half-life: Approx 7 hours

1. https://www.nejm.org/doi/full/10.1056/NEJMoa1915928
2. https://www.statpearls.com/ArticleLibrary/viewarticle/134517
3. http://www.druginformation.com/rxdrugs/V/Vericiguat Tablets.html#PD
4. https://reference.medscape.com/drug/verquvo-vericiguat-4000131
5. https://www.webmd.com/drugs/2/drug-180731/vericiguat-oral/details/list-contraindications