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

Abstract

Background-AZD1305 is an investigational antiarrhythmic agent for management of atrial fibrillation. It blocks various cardiac ion currents at different potencies and has atrial-predominant electrophysiological effects. We investigated the electrophysiological and proarrhythmic effects of AZD1305 versus dofetilide in dogs with chronic complete atrioventricular block and myocardial hypertrophic remodeling. Methods and Results-AZD1305 was administered to anesthetized mongrel dogs before and Ͼ2 weeks after the induction of atrioventricular block and ventricular and atrial electrophysiological parameters were assessed. In all dogs, the selective I Kr blocker dofetilide was used to examine susceptibility to acquired torsades de pointes in chronic atrioventricular block and for comparison.

Improved Prediction of Drug‐Induced Torsades de Pointes Through Simulations of Dynamics and Machine Learning Algorithms

“…Indeed, it has been known for years that the arrhythmogenicity of hERG block is mitigated by concurrent block of Na 1 or Ca 21 channels. 8,9 Recently, Kramer et al 10 published a predictive model that accounts for Ltype Ca 21 channel block in addition to hERG block. Their model improved discrimination between torsadogenic and nontorsadogenic drugs over the hERG assay, demonstrating that Ca 21 current block is a common mitigating factor in drug torsadogenicity.…”

“…A major shortcoming of the hERG assay is the failure to account for multichannel drug effects. Indeed, it has been known for years that the arrhythmogenicity of hERG block is mitigated by concurrent block of Na + or Ca 2+ channels . Recently, Kramer et al .…”

“…However, the mechanism of the protective effect of multichannel block is unclear. It is unlikely that it is purely due to diminished action potential (AP) prolongation, as in vivo studies show that multichannel block can reduce hERG block‐induced TdP without reduction of the QT interval . An alternative possibility is that the protective effect of multichannel block occurs via changes in ion concentration homeostasis.…”

In Silico Predictions and In Vivo Results of Drug–Drug Interactions by Ketoconazole and Verapamil on AZD1305, a Combined Ion Channel Blocker and a Sensitive CYP3A4 Substrate

“…With these features of the software, it is possible to complement preclinical data to make a judgment about the risk of drug–drug interactions of new compounds and also to optimize study design of clinical studies . We used in silico simulations (Simcyp) to assess the potential for PK interactions between AZD1305 (tert‐butyl [2‐{7‐(2‐[4‐cyano‐2‐fluorophenoxy]ethyl]‐9‐oxa‐3,7‐diazabicyclo(3.3.1)non‐3‐yl}ethyl]carbamate) and the CYP3A4 inhibitors ketoconazole and verapamil …”

“…[5][6][7][8] We used in silico simulations (Simcyp) to assess the potential for PK interactions between AZD1305 (tert-butyl [2-{7-(2-[4-cyano-2-fluorophenoxy]ethyl]-9-oxa-3,7diazabicyclo(3.3.1)non-3-yl}ethyl]carbamate) and the CYP3A4 inhibitors ketoconazole and verapamil. 9 AZD1305 is a combined ion channel blocking agent that was intended for rhythm control in atrial fibrillation. 10,11 In preclinical studies, AZD1305 terminated induced atrial fibrillation in dogs while showing a dose-dependent increase of the atrial effective refractory period.…”