Nonclinical proarrhythmia models: predicting Torsades de Pointes.

Area of Science:

• Cardiovascular Pharmacology
• Electrophysiology
• Drug Safety Assessment

Background:

• Prolongation of the QT interval and cardiac action potential are linked to Torsades de Pointes (TdP), a rare but fatal arrhythmia.
• Current nonclinical assays (e.g., hERG channel, APD, QT interval) predict QT prolongation but may not accurately assess TdP risk.
• Evidence suggests a dissociation between QT prolongation risk and torsadogenic risk, indicating limitations of existing assays.

Purpose of the Study:

• To review and discuss emerging in vitro and in vivo proarrhythmia models for predicting drug-induced TdP.
• To evaluate novel electrophysiological markers that may offer better prediction of TdP risk than standard assays.
• To examine the merits, shortcomings, and potential impact of these new models on drug safety assessment.

Main Methods:

• Review of three in vitro and three in vivo proarrhythmia models.
• Focus on electrophysiological markers such as transmural dispersion of repolarization, action potential triangulation, instability, reverse use-dependence, and early after-depolarizations.
• Discussion of reported correlations between model variables and clinical outcomes.

Main Results:

• Proarrhythmia models utilize electrophysiological markers that have shown correlation with clinical outcomes in predicting TdP risk.
• While models can discriminate between antiarrhythmic and nonarrhythmic drugs, independent external assessment is lacking.
• No single model has demonstrated clear superiority over others in predictive value.

Conclusions:

• Proarrhythmia models challenge current surrogates for TdP prediction and existing nonclinical strategies.
• Regulatory reluctance exists due to a lack of clear understanding and agreement on key proarrhythmic mechanisms.
• Further validation and mechanistic understanding are needed for wider acceptance and enhanced pharmaceutical decision-making in drug development.