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| Clinical data | |
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| Trade names | Brinavess |
| Other names | RSD1235 |
| Routes of administration | Intravenous,[1] |
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| Pharmacokinetic data | |
| Protein binding | low |
| Metabolism | CYP2D6,glucuronidation |
| Eliminationhalf-life | 3–5.5 hours |
| Identifiers | |
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| DrugBank |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.121.790 |
| Chemical and physical data | |
| Formula | C20H31NO4 |
| Molar mass | 349.471 g·mol−1 |
| 3D model (JSmol) | |
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Vernakalant, sold under the brand nameBrinavess, is aclass III antiarrhythmic drug for the acute conversion ofatrial fibrillation, in form of anintravenous infusion. It has been approved for use in the European Union and the United Kingdom since 2010. The USFood and Drug Administration denied approval in 2008 and 2019.
The drug is used for the treatment ofatrial fibrillation lasting up to three days in adults after heart surgery, or lasting up to seven days in other adults, as an intravenous infusion.[1]
Vernakalant is contraindicated in a number of heart conditions:
Vernakalant and other intravenous rhythm control drugs (class I andclass III antiarrhythmics) must not be given within four hours of each other.[1]
The most common adverse effects in studies weredysgeusia (taste disturbance, in 18% of patients), sneezing (13%) andparaesthesia (abnormal skin sensations, 7%); they were transient and rarely led to an abortion of the treatment. Potentially serious side effects included low blood pressure and conversion of the heart rhythm toatrial flutter instead of a normalsinus rhythm; flutter mostly responded to a second dose of vernakalant.[1]
There is a single case report of a person receiving an infusion of the full vernakalant dose in half the recommended time, resulting intachycardia (fast heartbeat) without lasting adverse effects.[1]
Drugs that inhibit theliver enzymeCYP2D6 might theoretically increase vernakalant concentrations in the body, as the latter is metabolized by this enzyme; but this has been found to be of no clinical significance. While the drug itself is a moderate CYP2D6 inhibitor, it is not expected to have a relevant impact on other pharmaceuticals that are broken down by this enzyme, because it only remains in the body for a short time. Vernakalant probably interacts with other antiarrhythmic drugs, although no formal studies have been done.[1]
Like otherclass III antiarrhythmics, vernakalant blocksatrialpotassium channels, thereby prolongingrepolarization. It differs from typical class III agents by blocking a certain type of potassium channel, thecardiac transient outward potassium current, with increased potency as the heart rate increases. This means that it is more effective at high heart rates, while other class III agents tend to lose effectiveness under these circumstances. It also slightly blocks thehERG potassium channel, leading to a prolongedQT interval. This may theoretically increase the risk ofventricular tachycardia, though this does not seem to be clinically relevant.[3]
The drug also blocks atrialsodium channels.[3]
After infusion, the substance is rapidly distributed in the body. In theblood serum, 53–56% are circulating freely and are not bound toplasma proteins. In people with normal CYP2D6 function, the main route of degradation is byO-demethylation via this enzyme. In 2D6poor metabolizers, vernakalant is mainly inactivated byglucuronidation and excreted by the kidney.Elimination half-life is three hours in 2D6 extensive (normal) metabolizers and 5.5 hours in poor metabolizers. The differences between poor and extensive metabolizers regarding peak concentrations,AUC and half-life are not clinically relevant.[1][4]
Vernakalant does not inhibit the enzymesCYP3A4,CYP1A2,CYP2C9,CYP2C19,CYP2E1, nor the transporter proteinP-gp.[1]
The molecule has threeasymmetric carbon atoms, allowing for 23 = 8stereomers. Thetrans stereomers are known to be pharmacologically active, but only theRRR-form is contained in the marketed formulation. TheSRR-form (with thehydroxyl group inS configuration) is a minor metabolite that is formed in the human body, mainly in poor metabolizers.[4]
The infusion contains vernakalanthydrochloride, which is highly water-soluble.[4]
Vernakalant was initially developed byCardiome Pharma, and theintravenous formulation was bought for further development byMerck in April 2009.[5] In September 2012, Merck terminated its agreements with Cardiome and has consequently returned all rights of the drug back to Cardiome, which as of 2018 is known asCorrevio Pharma.[citation needed]
In December 2007, the Cardiovascular and Renal Drugs Advisory Committee of the USFood and Drug Administration (FDA) voted to recommend the approval of vernakalant,[6] but in August 2008, the FDA judged that additional information was necessary for approval.[5] In the European Union, the medication was approved under the brand name Brinavess in September 2010.[7]
An oral formulation underwent phase IIclinical trials between 2005 and 2008.[8][9]
In December 2019, the resubmittedNew Drug Application for vernakalant was discussed by the Cardiovascular and Renal Drugs Advisory Committee.[10] The Advisory Committee voted not to recommend the approval.[11]