Key result
Non-clinical models quantify TdP risk to support regulatory evaluation of new compounds.
Why the study?
ICH S7B/E14 guidelines limited development of some compounds with unproven proarrhythmic risk, necessitating improved nonclinical proarrhythmic risk assessment models.
Comprehensive non-clinical models and surrogate markers are essential for predicting drug-induced torsade de pointes risk and complying with updated ICH regulatory guidelines.
Review of repolarization metrics beyond QT and proarrhythmic models may aid risk prediction; leaves open optimal clinical translation of in silico and animal models.
, and terminal repolarization period) besides QT interval. Finally, it presents various in silico, in vitro, ex vivo, and in vivo models for proarrhythmic risk prediction, such as comprehensive in vitro proarrhythmia assay in silico model, induced pluripotent stem cell-derived cardiomyocyte sheet, Langendorff-perfused heart preparation, chronic atrioventricular block animals (dogs, monkeys, pigs, and rabbits), acute atrioventricular block rabbits, methoxamine-sensitized rabbits, and genetically engineered rabbits for specific long QT syndromes. Those models along with the surrogate markers can play important roles in quantifying TdP risk of new compounds, impacting late-phase clinical design and regulatory decision-making, and preventing adverse events on postmarketing clinical use. SIGNIFICANCE STATEMENT: Since ICH S7B/E14 guidelines hampered the development of some potentially valuable compounds with unproven proarrhythmic risk, comprehensive in vitro proarrhythmia assay and exposure-response modeling were proposed in 2013 to reinforce proarrhythmic risk assessment of new compounds. In 2022, the ICH released questions and answers (stage 1), emphasizing a "double negative" nonclinical scenario for low-risk compounds, and new questions and answers (stage 2) for "non-double negative" compounds are expected. This review delves into proarrhythmic mechanisms with surrogate markers and explores various models for proarrhythmic risk prediction.
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Sugiyama et al. (2024) conducted a review in Drug-induced long QT syndrome. Non-clinical models for proarrhythmic risk prediction was evaluated. Non-clinical models, including in silico, in vitro, ex vivo, and in vivo assays, can quantify the torsade de pointes risk of new compounds to aid regulatory decision-making.
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