Abbott Laboratories, Abbott Park, IL 60064-6119, USA.
Br J Pharmacol. 2012 Nov;167(5):929-31. doi: 10.1111/j.1476-5381.2012.02096.x.
Reliable preclinical cardiac safety evaluations of drug candidates are essential for selecting the best therapeutic agents. Advanced automated patch clamp technologies now allow for characterizing drug effects on multiple cardiac currents, enabling subsequent simulations of integrated electrophysiological responses on cellular, tissue and organ levels. In this issue, Mirams et al. summarize the strengths and limitations of models and simulations predicting drug-induced electrophysiological responses, emphasizing delayed repolarization and Torsades de Pointes pro-arrhythmia. The utility of computational approaches is contingent upon realistic models of ventricular electrophysiology, robust characterization of drug-channel interactions and an understanding of channel-myocyte interactions and pro-arrhythmic mechanisms. Simulations evaluating effects on repolarization (hazard identification) should aid in selecting safer drug candidates early in drug discovery, while simulations evaluating risk of Torsades de Pointes (incorporating known risk factors) should quantify pro-arrhythmic risk and reduce the need for costly clinical QT studies later in development. The wider adoption of realistic models and simulation studies will depend on simulation performance compared with 'gold standard' clinical findings.
可靠的药物候选物临床前心脏安全性评估对于选择最佳治疗剂至关重要。先进的自动化膜片钳技术现在可以对多种心脏电流进行特征描述，从而可以对细胞、组织和器官水平的综合电生理反应进行后续模拟。在本期中，Mirams 等人总结了预测药物引起的电生理反应的模型和模拟的优缺点，强调了延迟复极和尖端扭转型室速的致心律失常作用。计算方法的实用性取决于心室电生理学的现实模型、药物-通道相互作用的稳健特征以及对通道-心肌细胞相互作用和致心律失常机制的理解。评估复极作用（危害识别）的模拟应有助于在药物发现早期选择更安全的候选药物，而评估尖端扭转型室速风险（包含已知风险因素）的模拟应量化致心律失常风险，并减少在开发后期进行昂贵的临床 QT 研究的需要。更广泛地采用现实模型和模拟研究将取决于与“金标准”临床发现相比的模拟性能。
