Drug-induced long QT syndrome: Concept and non-clinical models for predicting the onset of drug-induced torsade de pointes in patients in compliance with ICH E14/S7B guidance.

Abstract

ICH established S7B and E14 guidelines in 2005 to prevent drug-induced torsade de pointes (TdP), effectively preventing the development of high-risk drugs. However, those guidelines unfortunately hampered the development of some potentially valuable drug candidates despite not being proven to be proarrhythmic. In response, Comprehensive In Vitro Proarrhythmia Assay (CiPA) and Exposure-Response Modeling were proposed in 2013 to reinforce proarrhythmic risk assessment. In 2022, ICH released E14/S7B Q&As (Stage 1), emphasizing a "double negative" nonclinical scenario for low-risk compounds. For "non-double negative" compounds, new Q&As are expected to be enacted as Stage 2 shortly, in which more detailed recommendations for proarrhythmia models and proarrhythmic surrogate markers will be provided. This review details the onset mechanisms of drug-induced TdP, including I_Kr inhibition, pharmacokinetic factors, autonomic regulation and reduced repolarization reserve. It also explores the utility of proarrhythmic surrogate markers (J-T_peak, T_peak-T_end 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 CiPA in silico model, iPS 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 post-marketing clinical use. Significance Statement Since ICH S7B/E14 guidelines unfortunately 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, ICH released Q&As (Stage 1) emphasizing "double negative" nonclinical scenario for low-risk compounds, and new Q&As (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.