Abstract
There is currently a strong interest in using high-throughput in-vitro ion-channel screening data to make predictions regarding the cardiac toxicity potential of a new compound in both animal and human studies. A recent FDA think tank encourages the use of biophysical mathematical models of cardiac myocytes for this prediction task. However, it remains unclear whether this approach is the most appropriate. Here we examine five literature data-sets that have been used to support the use of four different biophysical models and one statistical model for predicting cardiac toxicity in numerous species using various endpoints. We propose a simple model that represents the balance between repolarisation and depolarisation forces and compare the predictive power of the model against the original results (leave-one-out cross-validation). Our model showed equivalent performance when compared to the four biophysical models and one statistical model. We therefore conclude that this approach should be further investigated in the context of early cardiac safety screening when in-vitro potency data is generated.
Highlights
The consequence of a drug carrying cardiac liability is a significant cause of concern to the Pharmaceutical industry
The strongest result can be seen for assessing whether a compound has a Torsades de Pointes risk or not
There is currently strong interest from both regulatory agencies and pharmaceutical companies in the use of in-silico models of cardiac myocytes as a tool for integrating the cardiac ion-channel liability of new compounds. This interest is motivated by the question of predicting the effects of a new compound’s cardiac risk in animal or man by using in-vitro ion-channel potency data (Cavero and Holzgrefe, 2014)
Summary
The consequence of a drug carrying cardiac liability is a significant cause of concern to the Pharmaceutical industry. The exact number of drugs that cause Torsades de Pointes is unknown, the CredibleMeds initiative (www.crediblemeds.org) has cataloged 42 drugs with a “Known Risk of Torsades de Pointes.”. These arrhythmias were mostly attributed to drugs causing significant prolongation to the QTc interval (time taken for ventricular depolarisation and repolaristaion), which is in turn related to the delay in repolarisation of the ventricular wall. Causative link was established with drug blocking of the hERG (human-ether-a-go-go) ion-channel within ventricular myocytes (Pollard et al, 2010). Initial screens focused only on the hERG channel but in recent years it has become apparent that other ion-channels might critically affect cardiac electrophysiology. Screenings have been extended to include these other ion-channels (Cavero and Holzgrefe, 2014)
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