Vernakalant Hydrochloride

IC50: Vernakalant inhibits two specific potassium currents, IKur (IC50 = 9 μΜ) and IKACh (ΙC50=10 μM) which are only present in atrial myocardium [1].
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. It also slightly blocks the hERG potassium channel, resulting in a prolonged QT interval. In addition, vernakalant also blocks atrial sodium channels.
In vitro: Previous study indicated that vernakalant showed selectivity for voltage-gated K+ channels, which were Kv1.5, Kv4.2, Kv4.3 and hERG channels, among which the Kv1.5 channel block was most potent. Such potent inhibitory effects occurred when the channel was probably in the activated state, since vernakalant caused a more pronounced reduction of the steady-state current amplitude in comparison to the early current [2].
Ex vivo: An previous ex vivo study of human atrial tissue from sinus rhythm and chronic atrial fibrillation indicated that the rate-dependent block of Na+ channels represented the main antiarrhythmic mechanism of vernakalant in the fibrillating atrium. In this study, vernakalant was found to prolong early repolarization in SR and AF, but late only in AF. Vernakalant did not reduce outward potassium currents compared with time-matched controls. However, area under the current–time curve was reduced due to acceleration of current decline with IC50s of 19 and 12 mM for SR and AF, respectively [3].
Clinical trial: Vernakalant (INN; codenamed RSD1235, proposed tradenames Kynapid and Brinavess), initially developed by Cardiome Pharma, is an investigational drug under regulatory review for the acute conversion of atrial fibrillation. Its intravenous formulation was later bought by Merck in April 2009. On December 2007, the Cardiovascular and Renal Drugs Advisory Committee of the US Food and Drug Administration (FDA) voted to recommend the approval of vernakalant, however, in August 2008 the FDA required necessary additional information for approval. Finially, on 1 September 2010, vernakalant under brand name Brinavess was approved in Europe. In addition, an oral formulation underwent Phase II clinical trials between 2005 and 2008.
Reference:
[1] Bronis, Kostas; Metaxa, Sofia; Koulouris, Spyridon; Manolis, Antonis S. Vernakalant: review of a novel atrial selective antiarrhythmic agent and its place in current treatment ofatrial fibrillation. Hospital Chronicles 2012, 7(3): 171−181
[2] Cheng JWM. Vernakalant in the management of atrial fibrillation. Ann Pharmacother 2008;42:533-42
[3] Wettwer E, Christ T, Endig S, Rozmaritsa N, Matschke K, Lynch JJ, Pourrier M, Gibson JK, Fedida D, Knaut M, Ravens U. The new antiarrhythmic drug vernakalant: ex vivo study of human atrial tissue from sinus rhythm and chronic atrial fibrillation. Cardiovasc Res. 2013;98(1):145-54.

Chemical cardioversion of recent-onset atrial fibrillation in the emergency department using vernakalant hydrochloride achieves safe and rapid restoration of sinus rhythm and facilitates same day discharge.[Pubmed:28168639]

Ir J Med Sci. 2017 Nov;186(4):903-908.

BACKGROUND: Vernakalant Hydrochloride is a rapid-acting antiarrhythmic drug licensed in the EU since 2010 for the conversion of recent-onset atrial fibrillation with proven efficacy and safety when compared with placebo and amiodarone in randomized clinical trials. AIMS: The aim of our study was to determine the feasibility of same day discharge (following 2 h monitoring) from the emergency department after successful cardioversion using Vernakalant Hydrochloride. METHODS: Patients with recent-onset atrial fibrillation treated in the emergency department of a large Dublin academic teaching hospital. Patients received a maximum of two weight based 10 min infusions of vernakalant. Hypotensive events (>30% initial blood pressure), arrhythmias, conversion rates, and time to conversion were recorded. RESULTS: Sinus rhythm was restored in 35 out of 42 patients (83%) in an average of 8.8 min (median 8 min), average CHA2DS2-VASc of 0.92, HAS-BLED of 0.21 and average symptoms duration of 12 h. There were no hypotensive or arrhythmogenic events. 41 out of 42 patients were discharged after 2 h of monitoring. CONCLUSIONS: Vernakalant Hydrochloride has provided a quick, safe, and practical means of achieving rapid restoration of sinus rhythm in our ED population with stable recent-onset AF who would otherwise not have undergone routine electrically cardioversion and same day discharge.

Population pharmacokinetic-pharmacodynamic analysis of vernakalant hydrochloride injection (RSD1235) in atrial fibrillation or atrial flutter.[Pubmed:21786177]

J Pharmacokinet Pharmacodyn. 2011 Oct;38(5):541-62.

Vernakalant Hydrochloride is a novel, relatively atrial-selective antiarrhythmic agent that rapidly converts atrial fibrillation (AF) to sinus rhythm (SR). This analysis integrates pharmacokinetic (PK) and safety data from 5 clinical trials of patients with AF or atrial flutter (AFL). Patients were initially given a 10-min intravenous (IV) infusion of vernakalant 3 mg/kg or placebo. If SR was not evident after a 15-min observation, then a second 10-min IV infusion of vernakalant 2 mg/kg or placebo was given. Population pharmacokinetic/pharmacodynamic (PK/PD) models were constructed for QT interval prolongation corrected for heart rate by Fridericia's formula (QTcF) and for changes in systolic blood pressure (SBP). The exposure-response relationships for QTcF and SBP were best described by sigmoidal maximum-effect (E (max)) models. For QTcF, the model was characterized by a typical E (max) of 20.3 ms, and by a vernakalant median effective concentration dependent (EC(5)(0)) on conversion status (4,222 ng/ml for patients converting to SR and 2,276 ng/ml for those remaining in AF/AFL). For SBP, the model was characterized by E (max) of 3.05 mmHg and EC(5)(0) of 1,141 ng/ml. Risk of hypotension (SBP <90 mmHg) was primarily associated with low baseline SBP and to a smaller extent with a history of congestive heart failure (CHF); plasma vernakalant concentrations showed a small contribution to the risk of hypotension (relative risk = 1.4 at 4,000 ng/ml), which may be significant with a baseline SBP of <105 mmHg. These results show that vernakalant had a smaller effect on QTcF in patients who demonstrated conversion to SR than those remaining in AF or AFL, and it had a relatively small effect on SBP.

Vernakalant hydrochloride to treat atrial fibrillation.[Pubmed:24617913]

Expert Opin Pharmacother. 2014 Apr;15(6):865-72.

INTRODUCTION: Intravenous vernakalant (Brinavess) has been developed and approved in Europe as a safe and efficacious drug to rapidly convert recent onset atrial fibrillation to sinus rhythm in patients with no minimal or structural heart disease. AREAS COVERED: The pharmacology of vernakalant and the pivotal Phase II and III clinical trials undertaken during its development are discussed with regard to safety and efficacy. An extensive PubMed search was used to identify suitable papers. EXPERT OPINION: As yet, there is no evidence of benefit over and above intravenous flecainide or propafenone for patients in whom vernakalant has a class 1a recommendation. As such, it is likely to be most useful in centres where only amiodarone is available.

Population pharmacokinetics of vernakalant hydrochloride injection (RSD1235) in patients with atrial fibrillation or atrial flutter.[Pubmed:21659624]

J Clin Pharmacol. 2012 Jul;52(7):1042-53.

Vernakalant Hydrochloride is a novel, predominantly atrial-selective antiarrhythmic drug that effectively and rapidly terminates atrial fibrillation (AF). Plasma vernakalant concentration data from 5 phase 2 and 3 clinical trials of vernakalant in patients with AF or atrial flutter and a phase 1 study in healthy volunteers were used to construct a population pharmacokinetic model. Plasma vernakalant concentration-time data were best fit by a 2-compartment mammillary model, with rapid first-order elimination from the central compartment. Median systemic clearance was 0.35 L/h/kg (or 28 L/h for an 80-kg patient), with intersubject variability estimated to be 40%. Clearance was significantly influenced by CYP2D6 genotype, age, serum creatinine concentration, and subject status (patient vs volunteer). The intercompartmental clearance was also influenced by subject status, whereas the volumes of the central compartment and peripheral compartment were unaffected by any covariates. Based on the final pharmacokinetic model, the area under the plasma vernakalant concentration-time curve from 0 to 90 minutes was estimated to be 15% higher in CYP2D6 poor metabolizers than extensive metabolizers, with age and serum creatinine having much smaller influences on exposure. These data suggest that dose adjustments based on patient characteristics, including use of concomitant drugs, are unnecessary for intravenous vernakalant.

Vernakalant hydrochloride is a mixed voltage- and frequency-dependent Na+ and atria-preferred K+ channel blocker. IC50 for block by Vernakalant of wild-type and mutant Kv1.5 channels Fractional block is 13.35±0.93 μM, 0.61±0.03 μM, and 1.63±0.09 μM for Kv1.5 channelwt, Kv1.5 channelI508F, Kv1.5 channelT479A, respectively.

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