Quantification of hERG Potassium Channel Block from the ECG

Blood potassium concentration ([K+]blood) influences the ECG T-wave morphology. T-wave slope-to-amplitude ratio (TS/A) has been shown to be correlated with [K+]blood, suggesting that it is a metric for the repolarizing IKr current, which flows through the hERG ion channels in cardiac cells. In this study we tested whether TS/A can also be used as an alternate ECG-based metric of the amount of hERG block in drug safety trials. We used data from two FDA-sponsored placebo-controlled cross-over studies, in which healthy subjects received a single or multiple doses of hERG-blocking drugs, either alone or in combination with compounds that block late sodium or calcium ion channels. TS/A was compared with other ECG markers for the ability to measure the amount of hERG block independent from other confounding ion channel block of the same drug or a combination of drugs. TS/A appeared to be exclusively sensitive to hERG block and independent of the drug type. It is a more accurate and stable ECG metric for hERG block than Tpeak-Tend, LRD30% and QTc (which is also sensitive to late sodium block). We conclude that TS/A should be added to the set of ECG markers measured in phase I drug safety trials.