Soubret Antoine, Helmlinger Gabriel, Dumotier Bérengère, Bibas Ruben, Georgieva Anna
Modeling and Simulation, Novartis Pharma AG, Basel, Switzerland.
Drug Metab Pharmacokinet. 2009;24(1):76-90. doi: 10.2133/dmpk.24.76.
Despite an impressive battery of preclinical cardiac electrophysiology experimental models and the assessment of QT during clinical trials, the risk of Torsades de Pointes (TdP), a potentially lethal ventricular arrhythmia, remains among the common reasons for drug market withdrawal or lack of approval. Due to the low prevalence of TdP, development of statistical evidence that other clinical markers could be better predictors of TdP has proven challenging. Preclinical studies have provided a deeper understanding of torsadogenic mechanisms and potential pro-arrhythmic markers to assess. Translating these preclinical insights into a quantitative clinical risk assessment remains challenging because of (i) species differences in cardiac electrophysiology and drug pharmacokinetics; and (ii) the inability to measure clinically specific cardiac electrophysiology metrics, and therefore ascertain the full predictive value of earlier preclinical components of the risk assessment process. The integrative capacity of cardiac electrophysiology modeling to span time and length scales may provide a quantitative and predictive framework, to complement expert-based preclinical-to-clinical cardiac risk assessment process. In this review, we present salient elements of this risk assessment process and describe essential components of cardiac electrophysiology modeling, to propose that a progressive integration of mechanistic components into a common quantitative framework may help improve the predictability of drug-induced TdP risk.
尽管有一系列令人印象深刻的临床前心脏电生理学实验模型以及在临床试验期间对QT间期的评估，但尖端扭转型室性心动过速（TdP）这一致命性室性心律失常的风险，仍然是药物退出市场或未获批准的常见原因之一。由于TdP的发病率较低，要得出其他临床指标可能是更好的TdP预测指标的统计学证据颇具挑战性。临床前研究对致心律失常机制和潜在的促心律失常标志物有了更深入的了解以供评估。将这些临床前见解转化为定量临床风险评估仍然具有挑战性，原因如下：（i）心脏电生理学和药物药代动力学存在种属差异；（ii）无法测量临床上特定的心脏电生理学指标，因此无法确定风险评估过程中早期临床前指标的全部预测价值。心脏电生理学建模跨越时间和长度尺度的整合能力，可能会提供一个定量和预测框架，以补充基于专家的临床前到临床的心脏风险评估过程。在本综述中，我们介绍了这一风险评估过程的要点，并描述了心脏电生理学建模的基本组成部分，提出将机制性组成部分逐步整合到一个通用的定量框架中，可能有助于提高药物诱发TdP风险的可预测性。
