Key result
Current pre-clinical biomarkers like hERG and in vivo QT assays are not fully predictive for torsades de pointes, highlighting the need for an integrated risk assessment strategy.
This review outlines an integrated pre-clinical strategy for pharmaceutical companies to assess the QT prolongation and proarrhythmic risk of new drug candidates using in vitro and in vivo assays.
May prompt reevaluation of single-assay cardiac safety screening in drug development; leaves open optimal integrated strategy for torsades prediction.
Since the Committee for Proprietary Medicinal Products (CPMP) of the European Union issued in 1997 a "points to consider" document for the assessment of the potential for QT interval prolongation by non-cardiovascular agents to predict drug-induced torsades de pointes (TdP), the QT liability has become the critical safety issue in the development of pharmaceuticals. As TdP is usually linked to delayed cardiac repolarization, international guideline (ICH S7B) has advocated the standard repolarization assays such as in vitro IKr (hERG current) and in vivo QT interval, or in vitro APD (as a follow up) as the best biomarkers for predicting the TdP risk. However, the recent increasing evidence suggests that the currently used above biomarkers and/or assays are not fully predictive for TdP, but also does not address potential new druginduced TdP due to the selective disruption of hERG protein trafficking to the cell membrane or VT and/or VF with QT shortening. There is, therefore, an urgent need for other surrogate markers or assays that can predict the proarrhythmic potential of drug candidate. In this review, we provide an ideal pre-clinical strategy to predict the potentials of QT liability and lethal arrhythmia of the drug candidates with recent issues in this field in mind, not at the expense of discarding therapeutically innovative drugs.
No takes yet. Share an insight, caveat, or question.
Takasuna et al. (2009) conducted a review in Drug-induced QT prolongation and torsades de pointes. Pre-clinical QT risk assessment assays was evaluated. Current pre-clinical biomarkers like hERG and in vivo QT assays are not fully predictive for torsades de pointes, highlighting the need for an integrated risk assessment strategy.