Assessment of the Ion Channel-blocking Profile of the Novel Combined Ion Channel Blocker AZD1305 and Its Proarrhythmic Potential Versus Dofetilide in the Methoxamine-sensitized Rabbit In Vivo

Abstract

AZD1305 is a novel antiarrhythmic agent under clinical evaluation for management of atrial fibrillation. This study assessed its ion channel-blocking potency by the whole cell patch-clamp technique in vitro and its proarrhythmic liability in anesthetized methoxamine-sensitized rabbits in comparison with dofetilide. AZD1305 predominantly blocked the hERG, the L-type calcium and the hNav1.5 currents in a concentration-dependent manner. In vivo AZD1305 increased the QT interval (from 145 +/- 8 to 196 +/- 18 ms, P < 0.01) without inducing ventricular extrasystoles or torsades de pointes (TdP). In contrast, dofetilide prolonged the QT interval from 161 +/- 3 to 256 +/- 15 ms (P < 0.001) and caused TdP in 12/17 rabbits (P < 0.01 vs. AZD1305). During AZD1305 and dofetilide infusion, the QTend-peak interval maximally increased by 14 +/- 4 and 30 +/- 6 ms (P < 0.05 vs. AZD1305) and the beat-by-beat QT interval variability (quantified as the short-term variability, STV) changed from 2 +/- 0.8 to 2 +/- 0.3 ms (NS) and from 2 +/- 0.2 to 12 +/- 1.1 ms (P < 0.001), respectively. Following dofetilide-induced TdP, 6 rabbits each were injected with saline or AZD1305. In contrast to saline, AZD1305 abbreviated the QT interval (from 275 +/- 25 to 216 +/- 9 ms, P < 0.05), reduced the STV to 1 +/- 0.1 ms (P < 0.001) and suppressed TdP in all 6 rabbits (P < 0.01 vs. saline). In conclusion, AZD1305 can be characterised as a combined ion channel blocker that delays repolarization without increasing beat-by-beat variability of repolarization (BVR) or inducing TdP whereas selective IKr blockade by dofetilide prolongs the QT interval and eventually increases BVR resulting in TdP.

Reduced Ventricular Proarrhythmic Potential of the Novel Combined Ion-Channel Blocker AZD1305 Versus Dofetilide in Dogs With Remodeled Hearts

“…9 In the anesthetized methoxamine-sensitized rabbit model of torsades de pointes ventricular tachyarrhythmia (TdP), intravenous AZD1305 increased the QT interval without inducing ventricular extrasystoles or TdP. 7 Beat-to-beat variability of repolarization duration (BVR of the QT interval) also remained unaltered. In contrast, the selective I Kr blocker dofetilide prolonged the QT interval, increased BVR, and induced TdP in the majority of animals tested.…”

“…Although AZD1305 predominantly blocks I Kr , it also has major inhibitory effects on I CaL and I Na (predominantly I NaLate ) and minor effects on other K ϩ currents. 7,8 In the normal canine heart, this compound exerts atrial-predominant electrophysiological effects both in vivo and in vitro. 9 In the anesthetized methoxamine-sensitized rabbit model of torsades de pointes ventricular tachyarrhythmia (TdP), intravenous AZD1305 increased the QT interval without inducing ventricular extrasystoles or TdP.…”

“…In contrast, the selective I Kr blocker dofetilide prolonged the QT interval, increased BVR, and induced TdP in the majority of animals tested. 7 AZD1305 has been shown to depress excitability and suppress delayedafterdepolarization-induced triggered activity in canine pulmonary-vein sleeve preparations. 10 Recent clinical data suggest that this compound has electrophysiological effects that may translate into antiarrhythmic efficacy in patients with AF and may have a reduced proarrhythmic potential as compared with selective I Kr blockers.…”

Comparison of different proarrhythmia biomarkers in isolated rabbit hearts

“…In the present study the I Kr 26 . However, sinus STV QT did not predict TdP in other studies utilizing a similar, anaesthetized rabbit model [27][28][29][30] .…”

“…It has been shown that beatto-beat variability of the repolarization measured in regular rhythm predicted TdP in clinical 24 and experimental 16,25,26 settings. However, beat-to-beat variability of repolarization measured in regular rhythm did not predict drug-induced TdP in anaesthetized rabbits [27][28][29][30] and guinea pigs 31 .…”