Vericiguat
Vericiguat Uses, Dosage, Side Effects, Food Interaction and all others data.
Vericiguat is a direct stimulator of soluble guanylate cyclase (sGC) used in the management of systolic heart failure to reduce mortality and hospitalizations. A key component of the NO-sGC-cGMP signaling pathway that helps to regulate the cardiovascular system, sGC enzymes are intracellular enzymes found in vascular smooth muscle cells (amongst other cell types) that catalyze the synthesis of cyclic guanosine monophosphate (cGMP) in response to activation by nitric oxide (NO). Cyclic GMP acts as a second messenger, activating a number of downstream signaling cascades that elicit a broad variety of effects, and these diverse cellular effects have implicated deficiencies in its production (primarily due to insufficient NO bioavailability) in the pathogenesis of various cardiovascular diseases. As a direct stimulator of sGC, vericiguat mitigates the need for a functional NO-sGC-cGMP axis and thereby helps to prevent the myocardial and vascular dysfunction associated with decreased sGC activity in heart failure.
Vericiguat was approved by the FDA in January 2021 - developed by Merck under the brand name Verquvo - for use in certain patients with systolic heart failure. Although not the first sGC stimulator to be granted FDA approval (riociguat was approved in 2013 for use in pulmonary hypertension), vericiguat is unique amongst its peers in that modifications to its structure have dramatically decreased its susceptibility to oxidative metabolism, resulting in a relatively long half-life and allowing for once-daily dosing.
By directly stimulating the increased production of intracellular cyclic guanosine monophosphate (cGMP), vericiguat causes the relaxation of vascular smooth muscle and vasodilation. Vericiguat has a relatively long half-life (~30h) that allows for once-daily dosing.
| Trade Name | Vericiguat |
| Availability | Prescription only |
| Generic | Vericiguat |
| Vericiguat Other Names | Vericiguat, Vériciguat, Vericiguatum |
| Related Drugs | Jardiance, Farxiga, empagliflozin, dapagliflozin, Verquvo |
| Weight | 10mg, 2.5mg, 5mg |
| Type | Oral tablet |
| Formula | C19H16F2N8O2 |
| Weight | Average: 426.388 Monoisotopic: 426.136428113 |
| Protein binding | Vericiguat is extensively (~98%) protein-bound in plasma, primarily to serum albumin. |
| Groups | Approved, Investigational |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Vericiguat is a soluble guanylate cyclase stimulator used to reduce heart failure-related hospitalization and cardiovascular death in patients with chronic systolic heart failure.
Vericiguat is indicated in adults with symptomatic, chronic heart failure and an ejection fraction of 5
Vericiguat is also used to associated treatment for these conditions: Cardiovascular Mortality, Heart Failure Hospitalization
How Vericiguat works
Heart failure (HF) involves, amongst other morphologic and physiologic changes, the impaired synthesis of nitric oxide (NO) and decreased activity of soluble guanylate cyclase (sGC). Functioning normally, NO binds to sGC and stimulates the synthesis of intracellular cyclic guanosine monophosphate (cGMP), a second messenger involved in the maintenance of vascular tone, as well as cardiac contractility and remodeling. Defects in this pathway are thought to contribute to the myocardial and vascular dysfunction associated with heart failure and are therefore a desirable target in its treatment.
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.
Toxicity
Data regarding overdosage with vericiguat are unavailable. Doses of up to 15mg once daily (50% greater than the recommended maintenance dose) have been studied and found to be well-tolerated. Symptoms of overdose are likely to be consistent with the adverse effect profile of vericiguat and may therefore involve significant hypotension for which symptomatic and supportive measures should be provided. Dialysis is unlikely to be of benefit in vericiguat overdose given its high degree of protein binding.
Food Interaction
- Take with food. Administration with food has been shown to reduce pharmacokinetic variability and significantly improve absorption.
[Moderate] ADJUST DOSING INTERVAL: Administration of vericiguat with food reduces its pharmacokinetic variability and increases its exposure.
Vericiguat is less soluble at neutral pH than at acidic pH.
Administration of vericiguat with a high-fat, high-calorie meal or low-fat, high-carbohydrate meal increased time to reach peak plasma concentration (Tmax) from about 1 hour (fasted) to about 4 hours (fed) and increased vericiguat systemic exposure (AUC) by 19% and peak plasma concentration (Cmax) by 9% for the 5 mg tablet and by 44% (AUC) and 41% (Cmax) for the 10 mg tablet as compared with the fasted state.
Concurrent treatment with drugs that increase gastric pH, such as proton pump inhibitors or antacids, decrease vericiguat AUC by about 30%.
Co-treatment with drugs that increase gastric pH did not affect vericiguat exposure in patients with heart failure when vericiguat was taken as directed with food.
MANAGEMENT: Administer vericiguat with food to ensure maximal exposure and decrease pharmacokinetic variability.
Vericiguat Disease Interaction
Volume of Distribution
In healthy subjects the steady-state volume of distribution of vericiguat is approximately 44 liters.
Elimination Route
Following the administration of 10mg of vericiguat by mouth once daily, the average steady-state Cmax and AUC in patients with heart failure is 350 mcg/L and 6,680 mcg•h/L, respectively, with a Tmax of 1 hour. The absolute bioavailability of orally-administered vericiguat is approximately 93% when taken with food - co-administration with meals has been shown to reduce pharmacokinetic variability, increase Tmax to roughly 4 hours, and increase Cmax and AUC by 41% and 44%, respectively.
Half Life
In patients with heart failure, the half-life of vericiguat is 30 hours.
Clearance
Vericiguat is a low-clearance drug, with an observed plasma clearance of 1.6 L/h in healthy volunteers and 1.3 L/h in patients with systolic heart failure.
Elimination Route
Following the oral administration of radiolabeled vericiguat, approximately 53% of the administered radioactivity was recovered in the urine and 45% in the feces. A human mass balance study found that the portion recovered in the urine comprised approximately 40.8% N-glucuronide metabolite, 7.7% other metabolites, and 9% unchanged parent drug, while virtually the entire portion recovered in the feces comprised unchanged vericiguat.
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