Cardiovascular Division School of Medicine Rayne Institute St Thomas' Hospital London SE17EH, UK.
Toxicol Appl Pharmacol. 2010 Mar 1;243(2):146-53. doi: 10.1016/j.taap.2009.12.002. Epub 2009 Dec 18.
Drug-induced torsades de pointes (TdP) is a syndrome that includes a potentially lethal cardiac arrhythmia. It has been identified as a possible adverse drug reaction (ADR) for drugs which affect the repolarization processes of the heart. In order to predict the potential for TdP liability, regulatory guidelines have been developed which require that new drugs be safety screened. Unfortunately, however, despite this requirement there are no validated preclinical models with TdP incidence as a hard endpoint. Therefore, surrogate biomarkers are used. The most common and eliciting the most discussion/controversy among cardiovascular scientists is the duration of the QT interval of the ECG. Since no single model is available to wholly assess drug-induced TdP liability, safety pharmacologists employ a battery of complementary preclinical models in order to develop an integrated risk assessment (IRA). Ideally, the IRA should be comprised of the results from the effects of the new chemical entity (NCE) on the human ether-a-go-go related (hERG) gene assay (actually a screen for block of the hERG gene product, the inward rectifying K current, IKr) and ECG effects in the conscious canine. However, since neither model is ideal the findings are generally supplemented by conduct of several additional experimental in vitro assays, namely the rabbit left ventricular wedge preparation, Langendorff isolated rabbit heart or isolated canine Purkinje fibre; nevertheless, as with many preclinical models, there is only limited validation and a resultant lack of general acceptance. Institution of regulatory guidance documents such as ICH S7A and S7B in conjunction with heightened awareness of the electrophysiological mechanisms that may be responsible for the development of TdP has led to a sharp fall in proarrhythmic compounds securing licensing, but at what costs? Supplementary experimental assays have furthered our understanding of drug-induced torsadogenesis, and it is now recognized that TdP is a multicausal event. This means that a perceived "positive" torsadogenic risk using one of the aforementioned models does not necessarily guarantee proarrhythmia. There has been an overall fall in the total number of NCEs pursued through development due to strict regulatory guidelines. Here we suggest that regulatory barriers can be alleviated by improving the integrated risk approach. But this requires better validation and deployment of existing preclinical models together with the invention of more precise and accurate models.
药物诱导的尖端扭转型室性心动过速（TdP）是一种综合征，包括潜在致命的心律失常。它已被确定为影响心脏复极化过程的药物的一种可能的药物不良反应（ADR）。为了预测 TdP 责任的潜力，已经制定了监管指南，要求对新药物进行安全性筛选。然而，尽管有这一要求，但没有以 TdP 发生率为硬终点的验证前临床模型。因此，使用替代生物标志物。最常见的也是心血管科学家最关注和最有争议的是心电图 QT 间期的持续时间。由于没有单一的模型可以完全评估药物引起的 TdP 责任，因此安全药理学家采用一系列互补的临床前模型来进行综合风险评估（IRA）。理想情况下，IRA 应包括新化学实体（NCE）对人类 ether-a-go-go 相关（hERG）基因检测（实际上是 hERG 基因产物，内向整流钾电流，IKr）和清醒犬 ECG 效应的影响的结果。然而，由于没有一个模型是理想的，因此一般通过进行几个额外的实验体外检测来补充发现，即兔左心室楔形制备、Langendorff 分离兔心或分离的犬浦肯野纤维；然而，与许多临床前模型一样，只有有限的验证，因此缺乏普遍接受。机构的监管指导文件，如 ICH S7A 和 S7B 与提高对可能导致 TdP 发展的电生理机制的认识相结合，导致心律失常化合物获得许可的数量急剧下降，但代价是什么？补充实验检测进一步加深了我们对药物诱导的扭转型心动过速发生机制的理解，现在人们认识到 TdP 是一个多因素事件。这意味着，使用上述模型之一检测到的“阳性”扭转型风险并不一定能保证心律失常。由于严格的监管指南，通过开发获得的新化学实体总数总体下降。在这里，我们建议通过改进综合风险方法来缓解监管障碍。但这需要更好地验证和部署现有的临床前模型，并发明更精确和准确的模型。
