International Life Sciences Institute (Health and Environmental Sciences Institute, HESI) initiative on moving towards better predictors of drug-induced torsades de pointes.

Knowledge of the cardiac safety of emerging new drugs is an important aspect of assuring the expeditious advancement of the best candidates targeted at unmet medical needs while also assuring the safety of clinical trial subjects or patients. Present methodologies for assessing drug-induced torsades de pointes (TdP) are woefully inadequate in terms of their specificity to select pharmaceutical agents, which are human arrhythmia toxicants. Thus, the critical challenge in the pharmaceutical industry today is to identify experimental models, composite strategies, or biomarkers of cardiac risk that can distinguish a drug, which prolongs cardiac ventricular repolarization, but is not proarrhythmic, from one that prolongs the QT interval and leads to TdP. To that end, the HESI Proarrhythmia Models Project Committee recognized that there was little practical understanding of the relationship between drug effects on cardiac ventricular repolarization and the rare clinical event of TdP. It was on that basis that a workshop was convened in Virginia, USA at which four topics were introduced by invited subject matter experts in the following fields: Molecular and Cellular Biology Underlying TdP, Dynamics of Periodicity, Models of TdP Proarrhythmia, and Key Considerations for Demonstrating Utility of Pre-Clinical Models. Contained in this special issue of the British Journal of Pharmacology are reports from each of the presenters that set out the background and key areas of discussion in each of these topic areas. Based on this information, the scientific community is encouraged to consider the ideas advanced in this workshop and to contribute to these important areas of investigations over the next several years.

Literature-based evaluation of four 'hard endpoint' models for assessing drug-induced torsades de pointes liability.

In safety pharmacology, a number of preclinical models for detecting drug-induced proarrhythmia liability have been recently introduced that utilize hard endpoints: early after depolarziations (EADs), torsades de pointes (TdP) or both as the principal biomarker. To explore the validity of four of the most common of these models, (the isolated canine/rabbit left ventricular wedge preparation, the isolated rabbit heart, the methoxamine-pretreated anaesthetized rabbit and the complete, chronic AV-blocked (CAVB) dog (conscious and anaesthetized), the present article reviews published data sets for three drugs with recognized and different human TdP liabilities (cisparide, terfenadine and moxifloxacinin). Finally, this review considers the value of inclusion of analysis of beat-to-beat variability of repolarization (BVR) in TdP liability testing to improve sensitivity and specificity.

Chronic amiodarone evokes no torsade de pointes arrhythmias despite QT lengthening in an animal model of acquired long-QT syndrome.

BACKGROUND: Amiodarone is an effective antiarrhythmic drug rarely associated with torsade de pointes arrhythmias (TdP). The noniodinated compound dronedarone could resemble amiodarone and be devoid of the adverse effects. In the dog with chronic complete atrioventricular (AV) block (CAVB) and acquired long-QT syndrome, the electrophysiological and proarrhythmic properties of the drugs were compared after 4 weeks of oral treatment. METHODS AND RESULTS: Amiodarone (n=7, 40 mg. kg(-1). d(-1)) and dronedarone (n=8, 20 mg/kg BID) were started at 6 weeks of CAVB (baseline). Six dogs served as controls. Surface ECGs and endocardially placed monophasic action potential catheters in the left (LV) and right (RV) ventricles were recorded to assess QTc time, action potential duration (APD), interventricular dispersion (DeltaAPD=LV APD minus RV APD), early afterdepolarizations (EADs), ectopic beats, and TdP. Both amiodarone (+21%) and dronedarone (+31%) increased QTc time. Amiodarone showed no increase in DeltaAPD in 4 of 7 dogs, whereas dronedarone augmented DeltaAPD in 7 of 8 animals. After dronedarone, TdP occurred in 4 of 8 dogs with the highest DeltaAPD (105+/-20 ms). TdP was never seen with amiodarone, not even in the dogs that had DeltaAPD values comparable to those with dronedarone. Furthermore, a difference existed in EADs and ectopic activity incidence (dronedarone 3 of 8; amiodarone 0 of 7), which was also seen during an epinephrine challenge. CONCLUSIONS: In the CAVB dog model, both amiodarone and dronedarone prolong QT time (class III effect). The absence of TdP with amiodarone seems to be related to homogeneous APD lengthening in the majority of dogs and the lack of EADs and/or ventricular ectopic beats in all.