Acute Canine Model for Drug-Induced Torsades de Pointes in Drug Safety Evaluation--Influences of Anesthesia and Validation with Quinidine and Astemizole

The electrical activity in the heart varies significantly between men and women and results in a sex-specific response to drugs. Recent evidence suggests that women are more than twice as likely as men to develop drug-induced arrhythmia with potentially fatal consequences. Yet, the sex-specific differences in drug-induced arrhythmogenesis remain poorly understood. Here we integrate multiscale modeling and machine learning to gain mechanistic insight into the sex-specific origin of drug-induced cardiac arrhythmia at differing drug concentrations. To quantify critical drug concentrations in male and female hearts, we identify the most important ion channels that trigger male and female arrhythmogenesis, and create and train a sex-specific multi-fidelity arrhythmogenic risk classifier. Our study reveals that sex differences in ion channel activity, tissue conductivity, and heart dimensions trigger longer QT-intervals in women than in men. We quantify the critical drug concentration for dofetilide, a high risk drug, to be seven times lower for women than for men. Our results emphasize the importance of including sex as an independent biological variable in risk assessment during drug development. Acknowledging and understanding sex differences in drug safety evaluation is critical when developing novel therapeutic treatments on a personalized basis. The general trends of this study have significant implications on the development of safe and efficacious new drugs and the prescription of existing drugs in combination with other drugs.

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Benchmark dose-response analyses for multiple endpoints in drug safety evaluation

Toxicology and Applied Pharmacology ◽

10.1016/j.taap.2021.115732 ◽

2021 ◽

pp. 115732

Author(s):

Antero Vieira Silva ◽

Joakim Ringblom ◽

Peter Moldeus ◽

Elin Törnqvist ◽

Mattias Öberg

Keyword(s):

Drug Safety ◽

Dose Response ◽

Safety Evaluation ◽

Benchmark Dose ◽

Multiple Endpoints ◽

Drug Safety Evaluation

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Antiarrhythmic and cardiac electrophysiological effects of SZV-270, a novel compound with combined Class I/B and Class III effects, in rabbits and dogs

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2020-0412 ◽

2020 ◽

Author(s):

Richard S Varga ◽

Tibor Hornyik ◽

Zoltán Husti ◽

Zsófia Kohajda ◽

Gábor Krajsovszky ◽

...

Keyword(s):

Torsades De Pointes ◽

Coronary Artery Occlusion ◽

Canine Model ◽

Artery Occlusion ◽

Class I ◽

Class Iii ◽

Drug Induced ◽

Pharmacological Management ◽

Repolarization Reserve ◽

Electrophysiological Effects

Cardiovascular diseases are the leading causes of mortality. Sudden cardiac death is most commonly caused by ventricular fibrillation (VF). Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major cause of stroke and heart failure. Pharmacological management of VF and AF remains suboptimal due to limited efficacy of antiarrhythmic drugs and their ventricular proarrhythmic adverse effects. In this study, the antiarrhythmic and cardiac cellular electrophysiological effects of SZV-270, a novel compound, were investigated in rabbit and canine models. SZV-270 significantly reduced the incidence of VF in rabbits subjected to coronary artery occlusion/reperfusion, reduced the incidence of burst-induced AF in a tachypaced conscious canine model of AF. SZV-270 prolonged frequency corrected QT interval, lengthened action potential duration and effective refractory period in ventricular and atrial preparations and blocked IKr in isolated cardiomyocytes (Class III effects), reduced maximum rate of depolarization (Vmax) at cycle lengths smaller than 1000 ms in ventricular preparations (Class I/B effect). Importantly, SZV-270 did not provoke Torsades de Pointes arrhythmia in an anesthetized rabbit proarrhythmia model characterized by impaired repolarization reserve. In conclusion, SZV-270 with its combined Class I/B and III effects can prevent re-entry arrhythmias with reduced risk of provoking drug-induced Torsades de Pointes.

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