Vernakalant

Vernakalant is an antiarrhythmic medicine that acts preferentially in the atria to prolong atrial refractoriness and to rate-dependently slow impulse conduction. These anti-fibrillatory actions on refractoriness and conduction are thought to suppress re-entry, and are potentiated in the atria during atrial fibrillation. The relative selectivity of vernakalant on atrial versus ventricular refractoriness is postulated to result from the block of currents regulated by ion channels that are expressed in the atria, but not in the ventricles, as well as the unique electrophysiologic condition of the fibrillating atria. However, blockade of cationic currents, including hERG channels and cardiac voltage-dependent sodium channels, which are present in the ventricles has been documented.

Pharmacodynamics effects

In preclinical studies, vernakalant blocks currents in all phases of the atrial action potential, including potassium currents that are expressed specifically in the atria (e.g. the ultra-rapid delayed rectifier and the acetylcholine dependent potassium currents). During atrial fibrillation, the frequency- and voltage-dependent block of sodium channels further focuses the action of the medicine toward rapidly activating and partially depolarized atrial tissue rather than toward the normally polarized ventricle beating at lower heart rates. Additionally, the ability of vernakalant to block the late component of the sodium current limits effects on ventricular repolarisation induced by blockade of potassium currents in the ventricle. Targeted effects on atrial tissue coupled with block of late sodium current suggests that vernakalant has a low proarrhythmic potential. Overall, the combination of effects of vernakalant on cardiac potassium and sodium currents results in substantial antiarrhythmic effects that are mainly concentrated in the atria.

In an electrophysiological study in patients, vernakalant significantly prolonged atrial effective refractory period in a dose-dependent manner, which was not associated with a significant increase in ventricular effective refractory period. Across the Phase 3 population, vernakalant treated patients had an increase in heart rate-corrected QT (using Fridericia’s correction, QTcF) compared to placebo (22.1 msec and 18.8 msec placebo-subtracted peaks after first and second infusions, respectively). By 90 minutes after the start of infusion, this difference was reduced to 8.1 msec.

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.

Distribution

Vernakalant is extensively and rapidly distributed in the body, with a volume of distribution of approximately 2 l/kg. The C_max and AUC were dose proportional between 0.5 mg/kg and 5 mg/kg. In patients, the typical total body clearance of vernakalant was estimated to be 0.41 l/hr/kg. The free fraction of vernakalant in human serum is 53-63% at concentration range of 1-5 μg/ml.

Elimination

Vernakalant is mainly eliminated by CYP2D6 mediated O-demethylation in CYP2D6 extensive metabolisers. Glucuronidation and renal excretion are the main mechanisms of elimination in CYP2D6 poor metabolisers. The mean elimination half-life of vernakalant in patients was approximately 3 hours in CYP2D6 extensive metabolisers and approximately 5.5 hours in poor metabolisers.

Special patient groups

Acute vernakalant pharmacokinetics is not significantly influenced by gender, history of congestive heart failure, renal impairment, or concomitant administration of beta blockers and other medications, including warfarin, metoprolol, furosemide and digoxin. In patients with hepatic impairment, exposures were elevated by 9 to 25%. No dose adjustment is required for these conditions, nor on the basis of age, serum creatinine or CYP2D6 metaboliser status.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single- and repeated-dose toxicity, and genotoxicity.

With respect to reproduction no effects on pregnancy, embryo-foetal development, parturition or postnatal development were observed after intravenous administration of vernakalant at exposure levels (AUC) similar or below the human exposure levels (AUC) achieved after a single intravenous dose of vernakalant. In embryo-foetal development studies with oral administration of vernakalant two times a day resulting in exposure levels (AUC) generally higher than those achieved in humans after a single intravenous dose of vernakalant malformations (misshapen/absent/fused skull bones including cleft palates, bent radius, bent/misshapen scapula, constricted trachea, absent thyroid, undescendent testes) occurred in rats and increased embryo-foetal lethality, increased number of foetuses with fused and/or additional sternebrae were seen in rabbits at the highest doses tested.