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Abstract:
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Some drugs will induce arrhythmia because of disrupting the regulation of the action potential. A typical type of proarrhythmia is named as “Torsade de Points (TdP)”, which can sometimes leads to sudden cardiac death. A typical non-clinical method to detect TdP risk is using safety margin defined by the ratio of hERG IC50, the half inhibitory concentration, and Cmax, hERG inhibition to the maximum free therapeutic concentration. Although there are large variability in the non-clinical assay and methods to calculate the margin, descriptive statistics is commonly used in the field.
We first compared different methods in deriving IC50/ safety margin based on dose-response curve, then discussed how to evaluate dose-response relation that incorporates uncertainty. Finally, by using Monte Carlo method to get distribution in the estimated safety margin, we classified the 28 drugs TdP risk using a two-pointer grid search method, and recommended the best criteria for drug TdP risk detection.
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