Vernakalant

Last updated

Vernakalant
Vernakalant.svg
Clinical data
Trade names Brinavess
Other namesRSD1235
Routes of
administration
Intravenous, [1]
ATC code
Legal status
Legal status
  • CA: ℞-only [2]
  • EU:Rx-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding low
Metabolism CYP2D6, glucuronidation
Elimination half-life 3–5.5 hours
Identifiers
  • (3R)-1-{(1R,2R)-2-[2-(3,4-dimethoxyphenyl)
    ethoxy]cyclohexyl}pyrrolidin-3-ol
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard 100.121.790 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C20H31NO4
Molar mass 349.471 g·mol−1
3D model (JSmol)
  • O(c1ccc(cc1OC)CCO[C@@H]3CCCC[C@H]3N2CC[C@@H](O)C2)C
  • InChI=1S/C20H31NO4/c1-23-19-8-7-15(13-20(19)24-2)10-12-25-18-6-4-3-5-17(18)21-11-9-16(22)14-21/h7-8,13,16-18,22H,3-6,9-12,14H2,1-2H3/t16-,17-,18-/m1/s1 X mark.svgN
  • Key:VBHQKCBVWWUUKN-KZNAEPCWSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Vernakalant, sold under the brand name Brinavess, is a class III antiarrhythmic drug for the acute conversion of atrial fibrillation, a kind of irregular heartbeat, in form of an intravenous infusion. It has been approved for use in the European Union and the United Kingdom since 2010. The US Food and Drug Administration denied approval in 2008 and 2019.

Contents

Medical uses

The drug is used for the treatment of atrial 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]

Contraindications

Vernakalant is contraindicated in a number of heart conditions:

Vernakalant and other intravenous rhythm control drugs (class I and class III antiarrhythmics) must not be given within four hours of each other. [1]

Side effects

The most common adverse effects in studies were dysgeusia (taste disturbance, in 18% of patients), sneezing (13%) and paraesthesia (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 to atrial flutter instead of a normal sinus rhythm; flutter mostly responded to a second dose of vernakalant. [1]

Overdose

There is a single case report of a person receiving an infusion of the full vernakalant dose in half the recommended time, resulting in tachycardia (fast heartbeat) without lasting adverse effects. [1]

Interactions

Drugs that inhibit the liver enzyme CYP2D6 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]

Pharmacology

Mechanism of action

Like other class III antiarrhythmics, vernakalant blocks atrial potassium channels, thereby prolonging repolarization. It differs from typical class III agents by blocking a certain type of potassium channel, the cardiac 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 the hERG potassium channel, leading to a prolonged QT interval. This may theoretically increase the risk of ventricular tachycardia, though this does not seem to be clinically relevant. [3]

The drug also blocks atrial sodium channels. [3]

Pharmacokinetics and pharmacogenomics

After infusion, the substance is rapidly distributed in the body. In the blood serum, 53–56% are circulating freely and are not bound to plasma proteins. In people with normal CYP2D6 function, the main route of degradation is by O-demethylation via this enzyme. In 2D6 poor metabolizers, vernakalant is mainly inactivated by glucuronidation 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 enzymes CYP3A4, CYP1A2, CYP2C9, CYP2C19, CYP2E1, nor the transporter protein P-gp. [1]

Chemistry

The molecule has three asymmetric carbon atoms, allowing for 23 = 8 stereomers. The trans stereomers are known to be pharmacologically active, but only the RRR-form is contained in the marketed formulation. The SRR-form (with the hydroxyl group in S configuration) is a minor metabolite that is formed in the human body, mainly in poor metabolizers. [4]

The infusion contains vernakalant hydrochloride, which is highly water-soluble. [4]

History

Vernakalant was initially developed by Cardiome Pharma, and the intravenous formulation was bought for further development by Merck 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 as Correvio Pharma.[ citation needed ]

In December 2007, the Cardiovascular and Renal Drugs Advisory Committee of the US Food 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 II clinical trials between 2005 and 2008. [8] [9]

In December 2019, the resubmitted New 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]

Related Research Articles

Antiarrhythmic agents, also known as cardiac dysrhythmia medications, are a class of drugs that are used to suppress abnormally fast rhythms (tachycardias), such as atrial fibrillation, supraventricular tachycardia and ventricular tachycardia.

<span class="mw-page-title-main">Dofetilide</span> Antiarrhythmic medication

Dofetilide is a class III antiarrhythmic agent. It is marketed under the trade name Tikosyn by Pfizer, and is available in the United States in capsules containing 125, 250, and 500 μg of dofetilide. It is not available in Europe or Australia.

<span class="mw-page-title-main">Quinidine</span> Antiarrythmic medication

Quinidine is a class IA antiarrhythmic agent used to treat heart rhythm disturbances. It is a diastereomer of antimalarial agent quinine, originally derived from the bark of the cinchona tree. The drug causes increased action potential duration, as well as a prolonged QT interval. As of 2019, its IV formulation is no longer being manufactured for use in the United States.

<span class="mw-page-title-main">Amiodarone</span> Antiarrhythmic medication used for various types of irregular heartbeats

Amiodarone is an antiarrhythmic medication used to treat and prevent a number of types of cardiac dysrhythmias. This includes ventricular tachycardia, ventricular fibrillation, and wide complex tachycardia, atrial fibrillation, and paroxysmal supraventricular tachycardia. Evidence in cardiac arrest, however, is poor. It can be given by mouth, intravenously, or intraosseously. When used by mouth, it can take a few weeks for effects to begin.

<span class="mw-page-title-main">Sotalol</span> Medication

Sotalol, sold under the brand name Betapace among others, is a medication used to treat and prevent abnormal heart rhythms. Evidence does not support a decreased risk of death with long term use. It is taken by mouth or given by injection into a vein.

<span class="mw-page-title-main">Procainamide</span> Medication to treat cardiac arrhythmias

Procainamide (PCA) is a medication of the antiarrhythmic class used for the treatment of cardiac arrhythmias. It is a sodium channel blocker of cardiomyocytes; thus it is classified by the Vaughan Williams classification system as class Ia. In addition to blocking the INa current, it inhibits the IKr rectifier K+ current. Procainamide is also known to induce a voltage-dependent open channel block on the batrachotoxin (BTX)-activated sodium channels in cardiomyocytes.

Proarrhythmia is a new or more frequent occurrence of pre-existing arrhythmias, paradoxically precipitated by antiarrhythmic therapy, which means it is a side effect associated with the administration of some existing antiarrhythmic drugs, as well as drugs for other indications. In other words, it is a tendency of antiarrhythmic drugs to facilitate emergence of new arrhythmias.

<span class="mw-page-title-main">Azimilide</span> Chemical compound

Azimilide is a class ΙΙΙ antiarrhythmic drug. The agents from this heterogeneous group have an effect on the repolarization, they prolong the duration of the action potential and the refractory period. Also they slow down the spontaneous discharge frequency of automatic pacemakers by depressing the slope of diastolic depolarization. They shift the threshold towards zero or hyperpolarize the membrane potential. Although each agent has its own properties and will have thus a different function.

<span class="mw-page-title-main">Levosimendan</span> Pharmaceutical drug

Levosimendan (INN) is a calcium sensitizer used in the management of acutely decompensated congestive heart failure. It is marketed under the trade name Simdax. Overall the drug has a two fold mechanism of action. It leads to greater inotropy by increasing the calcium sensitivity as it binds to troponin and this results in a greater positive inotrophic force. Secondly, the drug is able to open ATP sensitive potassium channels in vascular smooth muscle cells, and the vascular dilatory effects of the drug lead to a decreased preload and afterload, putting less work on the heart. This drug is in the process of review by the FDA but has not been approved for use in the United States yet.

<span class="mw-page-title-main">Acecainide</span> Antiarrythmic drug

Acecainide is an antiarrhythmic drug. Chemically, it is the N-acetylated metabolite of procainamide. It is a Class III antiarrhythmic agent, whereas procainamide is a Class Ia antiarrhythmic drug. It is only partially as active as procainamide; when checking levels, both must be included in the final calculation.

<span class="mw-page-title-main">Ibutilide</span> Chemical compound

Ibutilide is a Class III antiarrhythmic agent that is indicated for acute cardioconversion of atrial fibrillation and atrial flutter of a recent onset to sinus rhythm. It exerts its antiarrhythmic effect by induction of slow inward sodium current, which prolongs action potential and refractory period of myocardial cells. Because of its Class III antiarrhythmic activity, there should not be concomitant administration of Class Ia and Class III agents.

<span class="mw-page-title-main">Dronedarone</span> Medication

Dronedarone, sold under the brand name Multaq, is a class III antiarrhythmic medication developed by Sanofi-Aventis. It was approved by the US Food and Drug Administration (FDA) in July 2009. Besides being indicated in arrhythmias, it was recommended as an alternative to amiodarone for the treatment of atrial fibrillation and atrial flutter in people whose hearts have either returned to normal rhythm or who undergo drug therapy or electric shock treatment i.e. direct current cardioversion (DCCV) to maintain normal rhythm. It is a class III antiarrhythmic drug. The FDA label includes a claim for reducing hospitalization, but not for reducing mortality, as a reduction in mortality was not demonstrated in the clinical development program. A trial of the drug in heart failure was stopped as an interim analysis showed a possible increase in heart failure deaths, in people with moderate to severe congestive heart failure.

<span class="mw-page-title-main">Ranolazine</span> Drug used to treat angina

Ranolazine, sold under the brand name Ranexa among others, is a medication used to treat heart related chest pain. Typically it is used together with other medications when those are insufficient. Therapeutic benefits appear smaller in females than males. It is taken by mouth.

<span class="mw-page-title-main">Tedisamil</span> Chemical compound

Tedisamil (3,7-dicyclopropylmethyl-9,9-tetramethylene-3,7-diazabicyclo-3,3,1-nonane) is an experimental class III antiarrhythmic agent currently being investigated for the treatment of atrial fibrillation. Tedisamil blocks multiple types of potassium channels in the heart resulting in slowed heart rate. While the effects of tedisamil have been demonstrated in both atrial and ventricular muscle, repolarization is prolonged more efficiently in the atria. Tedisamil is administered intravenously and has a half-life of approximately 8 –13 hours in circulation. Tedisamil is being developed as an alternative to other antiarrhythmics as incidence of additional arrhythmic events is lower compared to other class III agents. Tedisamil also has significant anti-ischemic properties and was initially investigated as a potential treatment for angina until its antiarrhythmic effects were discovered. Tedisamil is manufactured by Solvay Pharmaceuticals Inc. under the proposed trade name Pulzium.

<span class="mw-page-title-main">Pilsicainide</span> Chemical compound

Pilsicainide (INN) is an antiarrhythmic agent. It is marketed in Japan as サンリズム (Sunrythm). It was developed by Suntory Holdings Limited and first released in 1991. The JAN applies to the hydrochloride salt, pilsicainide hydrochloride.

<span class="mw-page-title-main">Landiolol</span> Chemical compound

Landiolol (INN) is an ultra short-acting, β1-superselective intravenous adrenergic antagonist, which decreases the heart rate effectively with less negative effect on blood pressure or myocardial contractility. In comparison to other beta blockers, landiolol has the shortest elimination half-life, ultra-rapid onset of effect, and predictable effectiveness with inactive metabolites. The pure S-enantiomer structure of landiolol is believed to develop less hypotensive side effects in comparison to other β-blockers. This has a positive impact on the treatment of patients when reduction of heart rate without decrease in arterial blood pressure is desired. Landiolol was developed by modifying the chemical structure of esmolol to produce a compound with a higher rate of cardioselectivity and a greater potency without increasing its duration of action. It is sold as landiolol hydrochloride. Based on its positive benefit risk profile, landiolol has been granted the marketing authorization and introduced to the European markets under the brand names Rapibloc, Raploc, Runrapiq, Landibloc mid 2016. Landiolol is available in Japan under the brand names Onoact (50 mg) and Corbeta.

The management of atrial fibrillation (AF) is focused on preventing temporary circulatory instability, stroke and other ischemic events. Control of heart rate and rhythm are principally used to achieve the former, while anticoagulation may be employed to decrease the risk of stroke. Within the context of stroke, the discipline may be referred to as stroke prevention in atrial fibrillation (SPAF). In emergencies, when circulatory collapse is imminent due to uncontrolled rapid heart rate, immediate cardioversion may be indicated.

<span class="mw-page-title-main">Betrixaban</span> Chemical compound

Betrixaban is an oral anticoagulant drug which acts as a direct factor Xa inhibitor. Betrixaban is FDA approved for venous thrombosis prevention in adults hospitalized for an acute illness who are at risk for thromboembolic complications. Compared to other directly acting oral anticoagulants betrixaban has relatively low renal excretion and is not metabolized by CYP3A4.

<span class="mw-page-title-main">Celivarone</span> Experimental drug being tested for use in pharmacological antiarrhythmic therapy

Celivarone is an experimental drug being tested for use in pharmacological antiarrhythmic therapy. Cardiac arrhythmia is any abnormality in the electrical activity of the heart. Arrhythmias range from mild to severe, sometimes causing symptoms like palpitations, dizziness, fainting, and even death. They can manifest as slow (bradycardia) or fast (tachycardia) heart rate, and may have a regular or irregular rhythm.

<span class="mw-page-title-main">Budiodarone</span> Chemical compound

Budiodarone (ATI-2042) is an antiarrhythmic agent and chemical analog of amiodarone that is currently being studied in clinical trials. Amiodarone is considered the most effective antiarrhythmic drug available, but its adverse side effects, including hepatic, pulmonary and thyroid toxicity as well as multiple drug interactions, are discouraging its use. Budiodarone only differs in structure from amiodarone through the presence of a sec-butyl acetate side chain at position 2 of the benzofuran moiety. This side chain allows for budiodarone to have a shorter half-life in the body than amiodarone which allows it to have a faster onset of action and metabolism while still maintaining similar electrophysiological activity. The faster metabolism of budiodarone allows for fewer adverse side effects than amiodarone principally due to decreased levels of toxicity in the body.

References

  1. 1 2 3 4 5 6 7 8 "Brinavess: EPAR – Product information" (PDF). European Medicines Agency. 19 December 2019.
  2. "Heart health". Health Canada . 9 May 2018. Retrieved 13 April 2024.
  3. 1 2 Finnin M (July 2010). "Vernakalant: A novel agent for the termination of atrial fibrillation". American Journal of Health-System Pharmacy. 67 (14): 1157–64. doi:10.2146/ajhp080501. PMID   20592320.
  4. 1 2 3 "Brinavess: EPAR – Public assessment report" (PDF). European Medicines Agency. 25 June 2010.
  5. 1 2 "Merck and Cardiome Pharma Sign License Agreement for Vernakalant, an Investigational Drug for Treatment of Atrial Fibrillation". FierceBiotech. 9 April 2009. Retrieved 12 October 2010.
  6. "FDA Advisory Committee Recommends Approval of Kynapid for Acute Atrial Fibrillation". Drugs.com. Retrieved 15 March 2008.
  7. "Brinavess (vernakalant) for Infusion Approved in the European Union for Rapid Conversion of Recent Onset Atrial Fibrillation" (Press release). Merck & Co., Inc. 1 September 2010. Archived from the original on 28 September 2010. Retrieved 28 September 2010.
  8. Clinical trial number NCT00267930 for "Study of RSD1235-SR for the Prevention of Atrial Fibrillation/Atrial Flutter Recurrence" at ClinicalTrials.gov
  9. Clinical trial number NCT00526136 for "Vernakalant (Oral) Prevention of Atrial Fibrillation Recurrence Post-Conversion Study" at ClinicalTrials.gov
  10. "December 10, 2019 Meeting of the Cardiovascular and Renal Drugs Advisory Committee Meeting Announcement". FDA. Retrieved 9 December 2019.
  11. "FDA Panel Shoots Down Afib Cardioversion Drug Over Safety". MedPage Today. Retrieved 11 December 2019.