Vernakalant

Vernakalant

Clinical data
License data	EU EMA: Brinavess
Routes of administration	Intravenous, oral
ATC code	C01BG11 (WHO)
Legal status
Legal status	℞ (Prescription only)
Identifiers
IUPAC name (3R)-1-{(1R,2R)-2-[2-(3,4-dimethoxyphenyl) ethoxy]cyclohexyl}pyrrolidin-3-ol
CAS Number	794466-70-9 748810-28-8 (HCl)
PubChem (CID)	9930049
ChemSpider	8105680
UNII	9G468C8B13
ECHA InfoCard	100.121.790
Chemical and physical data
Formula	C20H31NO4
Molar mass	349.464 g/mol
3D model (Jmol)	Interactive image
SMILES O(c1ccc(cc1OC)CCO[C@@H]3CCCC[C@H]3N2CC[C@@H](O)C2)C
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 Key:VBHQKCBVWWUUKN-KZNAEPCWSA-N
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Vernakalant (INN; codenamed RSD1235, proposed tradenames Kynapid and Brinavess) is an investigational drug under regulatory review for the acute conversion of atrial fibrillation. It was initially developed by Cardiome Pharma, and the intravenous formulation was bought for further development by Merck in April 2009.^[1] In September 2012, Merck terminated its agreements with Cardiome and has consequently returned all rights of the drug back to Cardiome.

On 11 December 2007, the Cardiovascular and Renal Drugs Advisory Committee of the US Food and Drug Administration (FDA) voted to recommend the approval of vernakalant,^[2] but in August 2008 the FDA judged that additional information was necessary for approval.^[1] The drug (under brand name Brinavess) was approved in Europe on 1 September 2010.^[3]

An oral formulation underwent Phase II clinical trials between 2005 and 2008.^[4][5]

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.^[6]

The drug also blocks atrial sodium channels.^[6]

It's mainly used for rapid conversion of acute-onset AF (AF lasting 3 to 72 hours)

Metabolism

Vernakalant is cleared by both renal and hepatic mechanisms. Majority via cytochrome CYP2D6 and excreted as glucuronide. Elimination half life is 3-4 hours.

References

1. "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.
2. "FDA Advisory Committee Recommends Approval of Kynapid for Acute Atrial Fibrillation". Drugs.com. Retrieved 2008-03-15.
3. "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. Retrieved 28 September 2010.
4. Clinical trial number NCT00267930 for "Study of RSD1235-SR for the Prevention of Atrial Fibrillation/Atrial Flutter Recurrence" at ClinicalTrials.gov
5. Clinical trial number NCT00526136 for "Vernakalant (Oral) Prevention of Atrial Fibrillation Recurrence Post-Conversion Study" at ClinicalTrials.gov
6. Miki Finnin, Vernakalant: A Novel Agent for the Termination of Atrial Fibrillation: Pharmacology, Medscape Today, retrieved 12 October 2010