Holbrook Mark, Malik Marek, Shah Rashmi R, Valentin Jean-Pierre
Pfizer, Global Safety Pharmacology, Pfizer, PGRD, Sandwich, Kent, UK.
J Pharmacol Toxicol Methods. 2009 Jan-Feb;59(1):21-8. doi: 10.1016/j.vascn.2008.09.001. Epub 2008 Sep 17.
A session dedicated to the issue of drug-induced QT and/or QTc interval (QT/QTc) shortening of the electrocardiogram (ECG) was held at the 2007 Safety Pharmacology Society (SPS) meeting in Edinburgh.
The session included a presentation on the results of a cross company survey on QT/QTc-shortening, a podium debate with speakers arguing "for" and "against" QT/QTc shortening being a safety issue and a panel discussion with the audience.
Compared to QT/QTc prolongation, relatively little is known about the relevance to safety of drug-induced QT/QTc shortening. As with QT/QTc prolongation, there are genetic syndromes and pharmaceutical agents which cause shortening of QT/QTc. The potential safety issue of QT/QTc shortening and its suitability as a biomarker of drug-induced cardiac arrhythmias, are unclear, however, the type of arrhythmia associated with prolongation and shortening are thought to differ. Prolongation is associated with torsades de pointes, whereas, shortening of QT/QTc is proposed to be associated with the more severe arrhythmia, ventricular fibrillation (VF). The industry-wide survey (53 total responses representing 45 different companies) indicates that the number of compounds that induce QT/QTc shortening has increased over the past 5 years with 51% of responses reporting QT/QTc shortening in pre-clinical studies and 22% reporting a corresponding clinical experience. The reason for the increase is not clear but there is a clear business impact with 13% (7/56) of these compounds being discontinued in the pre-clinical phase due to QT/QTc shortening. The majority of companies with clinical experience of QT/QTc shortening have engaged with the regulatory agencies and these experiences will be valuable in shaping how the pharmaceutical industry and the agencies view drug-induced QT/QTc shortening in the future.
Currently it is not clear how much shortening of QT/QTc is required before it might be considered a safety issue and indeed, whether QT/QTc shortening is a suitable biomarker for cardiac arrhythmias. It is clear, however, that with our current understanding, compounds which shorten QT/QTc will attract close regulatory scrutiny and carry a business risk. The need to better understand this potential cardiac safety issue points to further research including; model development to determine the mechanism(s) of action of drug-induced QT/QTc shortening and the translation between the non-clinical and clinical situation.
在2007年于爱丁堡召开的安全药理学协会（SPS）会议上，举办了一场专门讨论药物诱导心电图（ECG）QT和/或QTc间期缩短问题的会议。
该会议包括一场关于QT/QTc缩短的跨公司调查结果的报告、一场讲台辩论（辩手分别支持和反对QT/QTc缩短是一个安全问题）以及一场与观众的小组讨论。
与QT/QTc延长相比，人们对药物诱导的QT/QTc缩短与安全性的相关性了解较少。与QT/QTc延长一样，存在导致QT/QTc缩短的遗传综合征和药物制剂。然而，QT/QTc缩短的潜在安全问题及其作为药物诱导心律失常生物标志物的适用性尚不清楚，不过，与延长和缩短相关的心律失常类型被认为有所不同。QT延长与尖端扭转型室速相关，而QT/QTc缩短则被认为与更严重的心律失常——心室颤动（VF）相关。全行业调查（共收到53份回复，代表45家不同公司）表明，在过去5年中，诱导QT/QTc缩短的化合物数量有所增加，51%的回复报告在临床前研究中出现QT/QTc缩短，22%报告有相应的临床经验。增加的原因尚不清楚，但存在明显的商业影响，这些化合物中有13%（7/56）因QT/QTc缩短在临床前阶段被停用。大多数有QT/QTc缩短临床经验的公司已与监管机构进行了沟通，这些经验对于塑造制药行业和监管机构未来对药物诱导的QT/QTc缩短问题的看法将具有重要价值。
目前尚不清楚QT/QTc缩短到何种程度才可能被视为一个安全问题，实际上，QT/QTc缩短是否是心律失常的合适生物标志物也不明确。然而，很明显，就我们目前的理解而言，缩短QT/QTc的化合物将受到严格的监管审查，并带来商业风险。更好地理解这一潜在心脏安全问题的必要性指向了进一步的研究，包括：开发模型以确定药物诱导QT/QTc缩短的作用机制，以及非临床和临床情况之间的转化。
