The continuing evolution of torsades de pointes liability testing methods: Is there an end in sight?


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Abstract

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.

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