Identification
- Summary
Vernakalant is an antiarrhythmic medication used to treat patients with atrial fibrillation.
- Brand Names
- Brinavess
- Generic Name
- Vernakalant
- DrugBank Accession Number
- DB06217
- Background
Vernakalant was developed by Cardiome Pharma as as an antiarrhythmic drug intended for rapid conversion of atrial fibrillation to sinus rhythm. It acts as an atypical class III antiarrhythmic drug that potentiates its effect in higher heart rates. Intravenous formulation was approved in Europe in September 2010 as Brinavess and in Canada in April 2017. It is an investigational drug under regulatory review by FDA.
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Vernakalant (DB06217)
- Weight
- Average: 349.471
Monoisotopic: 349.225308482 - Chemical Formula
- C20H31NO4
- Synonyms
- (3R)-1-((1R,2R)-2-(2-(3,4-dimethoxyphenyl)ethoxy)cyclohexyl)pyrrolidin-3-ol
- Vernakalant
Pharmacology
- Indication
Indicated for the rapid conversion of recent onset of atrial fibrillation to sinus rhythm in adults for non-surgery patients that lasts for less than 7 days of duration and post-cardiac surgery patients with atrial fibrillation lasting less than 3 days of duration.
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Management of Atrial fibrillation •••••••••••• - Contraindications & Blackbox Warnings
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Vernakalant blocks currents in all phases of atrial action potential including atria-specific potassium currents (the ultra-rapid delayed rectifier and the acetylcholine dependent potassium currents) and prolongs the refractory period. It dose-dependently prolongs atrial refractoriness, prolongs AV nodal conduction and refractoriness, and slightly prolongs QRS duration without significantly affecting ventricular refractory period. Vernakalant has a high affinity to ion channels specifically involved in repolarization of atrial tissue and is thought to have a low proarrhythmic potential.
- Mechanism of action
Vernakalant blocks atrial voltage-gated sodium channels in a dose and frequency-dependent manner and inhibits late sodium current (INa)which confers its effect on intra-atrial conduction. This current blockade enhance and onset of drug action accelerates in higher heart rate as the affinity of vernakalant for INa also increases. Its binding offset is quick once the heart rate slows 8. It also blocks Kv 1.5 channel and its early activating potassium channels (IKur) and inhibits acetylcholine-activated potassium channels (IKAch), which are specific to the atrium and cause prolongation of atrial refractoriness. Vernakalant also blocks Kv4.3 channel and its cardiac transient outward potassium current (Ito), which is involved more with atrial than ventricular refractoriness 9. Vernakalant minimally blocks hERG channels and its rapidly activating/delayed rectifying potassium current (IKr) which accounts for mild QT prolongation. QRS widening due to INa blockade also contributes to QT prolongation 6.
Target Actions Organism ASodium channel protein type 5 subunit alpha blockerHumans APotassium voltage-gated channel subfamily A member 5 blockerHumans APotassium voltage-gated channel subfamily D member 3 blockerHumans UPotassium voltage-gated channel subfamily H member 2 blockerHumans - Absorption
In patients, average peak plasma concentrations of vernakalant were 3.9 μg/ml following a single 10 minute infusion of 3 mg/kg vernakalant hydrochloride, and 4.3 μg/ml following a second infusion of 2 mg/kg with a 15 minute interval between doses 10.
- Volume of distribution
Approximately 2L/kg.
- Protein binding
Displays low protein binding and the free fraction of vernakalant in human serum is 53-63% at concentration range of 1-5 μg/ml.
- Metabolism
Vernakalant is mainly eliminated by CYP2D6 mediated O-demethylation in CYP2D6 extensive metabolisers. Glucuronidation is the main metabolism pathway in CYP2D6 poor metabolisers.
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- Route of elimination
Mainly eliminated via renal excretion.
- Half-life
Elimination half life in CYP2D6 extensive metabolizers is 3 hours and 5.5 hours in poor metabolizers.
- Clearance
The typical total body clearance of vernakalant was estimated to be 0.41 l/hr/kg.
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
Some common unwanted effects include hypotension, ventricular arrhythmias, bradycardia, atrial flutter, dysgeusia, paraesthesia, dizziness and nausea.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbatacept The metabolism of Vernakalant can be increased when combined with Abatacept. Abiraterone The metabolism of Vernakalant can be decreased when combined with Abiraterone. Acebutolol Acebutolol may increase the arrhythmogenic activities of Vernakalant. Acetaminophen The metabolism of Vernakalant can be decreased when combined with Acetaminophen. Acetyldigitoxin Acetyldigitoxin may increase the arrhythmogenic activities of Vernakalant. - Food Interactions
- No interactions found.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Vernakalant hydrochloride 7G4J1ZD9UQ 748810-28-8 JMHYCBFEEFHTMK-IIUXMCBISA-N - International/Other Brands
- Kynapid (Cardiome Pharma Corp.)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Brinavess Solution 20 mg / mL Intravenous Cipher Pharmaceuticals Inc. 2018-01-23 Not applicable Canada 
Brinavess Injection, solution, concentrate 20 mg/ml Intravenous Correvio 2020-12-20 Not applicable EU 
Brinavess Injection, solution, concentrate 20 mg/ml Intravenous Correvio 2020-12-20 Not applicable EU
Categories
- ATC Codes
- C01BG11 — Vernakalant
- Drug Categories
- Antiarrhythmic agents
- Antiarrhythmics, Class III
- Benzene Derivatives
- Cardiac Therapy
- Cytochrome P-450 CYP2D6 Inhibitors
- Cytochrome P-450 CYP2D6 Inhibitors (strength unknown)
- Cytochrome P-450 CYP2D6 Substrates
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Ethers
- Methyl Ethers
- Phenols
- Phenyl Ethers
- Potential QTc-Prolonging Agents
- QTc Prolonging Agents
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as tyrosols and derivatives. These are compounds containing a hydroxyethyl group attached to the C4 carbon of a phenol group.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Phenols
- Sub Class
- Tyrosols and derivatives
- Direct Parent
- Tyrosols and derivatives
- Alternative Parents
- Dimethoxybenzenes / Phenoxy compounds / Anisoles / Cyclohexylamines / Alkyl aryl ethers / N-alkylpyrrolidines / Trialkylamines / Secondary alcohols / 1,2-aminoalcohols / Dialkyl ethers show 3 more
- Substituents
- 1,2-aminoalcohol / Alcohol / Alkyl aryl ether / Amine / Anisole / Aromatic heteromonocyclic compound / Azacycle / Cyclohexylamine / Dialkyl ether / Dimethoxybenzene show 19 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 9G468C8B13
- CAS number
- 794466-70-9
- InChI Key
- VBHQKCBVWWUUKN-KZNAEPCWSA-N
- InChI
- 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
- IUPAC Name
- (3R)-1-[(1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl]pyrrolidin-3-ol
- SMILES
- COC1=C(OC)C=C(CCO[C@@H]2CCCC[C@H]2N2CC[C@@H](O)C2)C=C1
References
- General References
- Naccarelli GV, Wolbrette DL, Samii S, Banchs JE, Penny-Peterson E, Stevenson R, Gonzalez MD: Vernakalant--a promising therapy for conversion of recent-onset atrial fibrillation. Expert Opin Investig Drugs. 2008 May;17(5):805-10. doi: 10.1517/13543784.17.5.805 . [Article]
- Cheng JW: Vernakalant in the management of atrial fibrillation. Ann Pharmacother. 2008 Apr;42(4):533-42. doi: 10.1345/aph.1K542. Epub 2008 Mar 11. [Article]
- Dorian P, Pinter A, Mangat I, Korley V, Cvitkovic SS, Beatch GN: The effect of vernakalant (RSD1235), an investigational antiarrhythmic agent, on atrial electrophysiology in humans. J Cardiovasc Pharmacol. 2007 Jul;50(1):35-40. [Article]
- Orth PM, Hesketh JC, Mak CK, Yang Y, Lin S, Beatch GN, Ezrin AM, Fedida D: RSD1235 blocks late INa and suppresses early afterdepolarizations and torsades de pointes induced by class III agents. Cardiovasc Res. 2006 Jun 1;70(3):486-96. Epub 2006 Feb 14. [Article]
- Savelieva I, Graydon R, Camm AJ: Pharmacological cardioversion of atrial fibrillation with vernakalant: evidence in support of the ESC Guidelines. Europace. 2014 Feb;16(2):162-73. doi: 10.1093/europace/eut274. Epub 2013 Oct 9. [Article]
- Camm AJ: The vernakalant story: how did it come to approval in Europe and what is the delay in the U.S.A? Curr Cardiol Rev. 2014 Nov;10(4):309-14. [Article]
- Tsuji Y, Dobrev D: Safety and efficacy of vernakalant for acute cardioversion of atrial fibrillation: an update. Vasc Health Risk Manag. 2013;9:165-75. doi: 10.2147/VHRM.S43720. Epub 2013 Apr 23. [Article]
- Finnin M: Vernakalant: A novel agent for the termination of atrial fibrillation. Am J Health Syst Pharm. 2010 Jul 15;67(14):1157-64. doi: 10.2146/ajhp080501. [Article]
- Dia E.Q., Rathbun R.A., Song J.C.: Vernakalant: A novel antiarrhythmic agent for the treatment of atrial fibrillation Formulary. 2007 August 1;42:475-483. [Article]
- European Medicines Agency Summary of product characteristics [Link]
- External Links
- KEGG Drug
- D06665
- PubChem Compound
- 9930049
- PubChem Substance
- 347827765
- ChemSpider
- 8105680
- ChEBI
- 135956
- ChEMBL
- CHEMBL2111112
- ZINC
- ZINC000022010910
- Wikipedia
- Vernakalant
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 4 Completed Treatment Atrial Fibrillation 1 4 Completed Treatment Paroxysmal Atrial Fibrillation (PAF) 1 4 Recruiting Treatment Atrial Fibrillation 1 4 Unknown Status Diagnostic Atrial Fibrillation 1 4 Withdrawn Treatment Atrial Fibrillation 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, solution, concentrate Intravenous Injection, solution, concentrate Intravenous 20 mg/ml Solution Intravenous 20 mg / mL - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.156 mg/mL ALOGPS logP 2.74 ALOGPS logP 2.51 Chemaxon logS -3.4 ALOGPS pKa (Strongest Acidic) 14.85 Chemaxon pKa (Strongest Basic) 9.65 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 51.16 Å2 Chemaxon Rotatable Bond Count 7 Chemaxon Refractivity 98.27 m3·mol-1 Chemaxon Polarizability 39.63 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.9879 Blood Brain Barrier + 0.8078 Caco-2 permeable - 0.5127 P-glycoprotein substrate Substrate 0.7152 P-glycoprotein inhibitor I Non-inhibitor 0.5542 P-glycoprotein inhibitor II Inhibitor 0.9347 Renal organic cation transporter Non-inhibitor 0.517 CYP450 2C9 substrate Non-substrate 0.6724 CYP450 2D6 substrate Non-substrate 0.6158 CYP450 3A4 substrate Substrate 0.7177 CYP450 1A2 substrate Non-inhibitor 0.6988 CYP450 2C9 inhibitor Non-inhibitor 0.8906 CYP450 2D6 inhibitor Non-inhibitor 0.5583 CYP450 2C19 inhibitor Non-inhibitor 0.5335 CYP450 3A4 inhibitor Non-inhibitor 0.6027 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.5399 Ames test Non AMES toxic 0.7665 Carcinogenicity Non-carcinogens 0.9268 Biodegradation Not ready biodegradable 0.9758 Rat acute toxicity 2.6465 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.688 hERG inhibition (predictor II) Inhibitor 0.7926
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 186.207304 predictedDarkChem Lite v0.1.0 [M-H]- 188.82907 predictedDeepCCS 1.0 (2019) [M-H]- 186.207304 predictedDarkChem Lite v0.1.0 [M-H]- 188.82907 predictedDeepCCS 1.0 (2019) [M+H]+ 185.892404 predictedDarkChem Lite v0.1.0 [M+H]+ 191.18709 predictedDeepCCS 1.0 (2019) [M+H]+ 185.892404 predictedDarkChem Lite v0.1.0 [M+H]+ 191.18709 predictedDeepCCS 1.0 (2019) [M+Na]+ 186.099404 predictedDarkChem Lite v0.1.0 [M+Na]+ 198.19194 predictedDeepCCS 1.0 (2019) [M+Na]+ 186.099404 predictedDarkChem Lite v0.1.0 [M+Na]+ 198.19194 predictedDeepCCS 1.0 (2019)
Targets
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Use our structured and evidence-based datasets to unlock newinsights and accelerate drug research.
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- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Blocker
- General Function
- Voltage-gated sodium channel activity involved in sa node cell action potential
- Specific Function
- This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the pr...
- Gene Name
- SCN5A
- Uniprot ID
- Q14524
- Uniprot Name
- Sodium channel protein type 5 subunit alpha
- Molecular Weight
- 226937.475 Da
References
- Finnin M: Vernakalant: A novel agent for the termination of atrial fibrillation. Am J Health Syst Pharm. 2010 Jul 15;67(14):1157-64. doi: 10.2146/ajhp080501. [Article]
- Dia E.Q., Rathbun R.A., Song J.C.: Vernakalant: A novel antiarrhythmic agent for the treatment of atrial fibrillation Formulary. 2007 August 1;42:475-483. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Blocker
- General Function
- Voltage-gated potassium channel activity involved in sa node cell action potential repolarization
- Specific Function
- Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes. Forms tetrameric potassium-selective channels through which potassium ions pass in accordance...
- Gene Name
- KCNA5
- Uniprot ID
- P22460
- Uniprot Name
- Potassium voltage-gated channel subfamily A member 5
- Molecular Weight
- 67227.15 Da
References
- Eldstrom J, Wang Z, Xu H, Pourrier M, Ezrin A, Gibson K, Fedida D: The molecular basis of high-affinity binding of the antiarrhythmic compound vernakalant (RSD1235) to Kv1.5 channels. Mol Pharmacol. 2007 Dec;72(6):1522-34. Epub 2007 Sep 14. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Blocker
- General Function
- Metal ion binding
- Specific Function
- Pore-forming (alpha) subunit of voltage-gated rapidly inactivating A-type potassium channels. May contribute to I(To) current in heart and I(Sa) current in neurons. Channel properties are modulated...
- Gene Name
- KCND3
- Uniprot ID
- Q9UK17
- Uniprot Name
- Potassium voltage-gated channel subfamily D member 3
- Molecular Weight
- 73450.53 Da
References
- Dia E.Q., Rathbun R.A., Song J.C.: Vernakalant: A novel antiarrhythmic agent for the treatment of atrial fibrillation Formulary. 2007 August 1;42:475-483. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Blocker
- General Function
- Voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization
- Specific Function
- Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the ...
- Gene Name
- KCNH2
- Uniprot ID
- Q12809
- Uniprot Name
- Potassium voltage-gated channel subfamily H member 2
- Molecular Weight
- 126653.52 Da
References
- Dia E.Q., Rathbun R.A., Song J.C.: Vernakalant: A novel antiarrhythmic agent for the treatment of atrial fibrillation Formulary. 2007 August 1;42:475-483. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- General Function
- Steroid hydroxylase activity
- Specific Function
- Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
- Gene Name
- CYP2D6
- Uniprot ID
- P10635
- Uniprot Name
- Cytochrome P450 2D6
- Molecular Weight
- 55768.94 Da
References
- Mao ZL, Wheeler JJ, Clohs L, Beatch GN, Keirns J: Pharmacokinetics of novel atrial-selective antiarrhythmic agent vernakalant hydrochloride injection (RSD1235): influence of CYP2D6 expression and other factors. J Clin Pharmacol. 2009 Jan;49(1):17-29. doi: 10.1177/0091270008325148. Epub 2008 Oct 16. [Article]
Drug created at March 19, 2008 16:17 / Updated at February 20, 2024 23:54