Drug-induced long QT syndrome: Concept and nonclinical models for predicting the onset of drug-induced torsade de pointes in patients in compliance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E14/S7B guidance.

Abstract

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (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 hampered the development of some potentially valuable drug candidates despite not being proven to be proarrhythmic. In response, comprehensive in vitro proarrhythmia assay and exposure-response modeling were proposed in 2013 to reinforce proarrhythmic risk assessment. In 2022, the ICH released E14/S7B questions and answers (stage 1), emphasizing a "double negative" nonclinical scenario for low-risk compounds. For "non-double negative" compounds, new questions and answers 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 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.