Improving assessment of cardiovascular arrhythmic safety of new pharmacologic agents

Sammanfattning: Fourteen drugs have been removed from the market worldwide due to an increased risk of torsade de pointes (TdP), a potentially fatal ventricular arrhythmia. Almost all of the removed drugs that have been linked to an increased risk for TdP have been shown to block the human ether-à-go-go-related gene (hERG) potassium channel. In addition, block of the hERG potassium channel results in a prolongation of the duration of ventricular repolarization measured as the QT interval on the electrocardiogram (ECG). Therefore, almost all new drugs must be studied in a thorough QT (TQT) study to determine if they have the potential to prolong the heart rate corrected QT interval (QTc). The TQT study is an expensive study that in addition to including a negative control (placebo), also includes a positive pharmacologic control to ensure assay sensitivity and proper study conduct. Not all drugs that block the hERG potassium channel and prolong the QTc interval have been linked with a risk for TdP likely due to additional inward current block. For example block of the late sodium (amiodarone, ranolazine) or L-type calcium (verapamil). In addition, not every study is able to detect the QTc prolongation associated with the positive pharmacological control. It is unknown which factors have a greater influence on study quality and the ability to demonstrate assay sensitivity. TQT studies from the Food and Drug Administration (FDA) ECGWarehouse were used to investigate factors of assay sensitivity and how they relate to ECG quality metrics, as well as new ECG biomarkers that could complement the QTc interval and increase specificity of the TQT study. In addition, two prospective clinical trials were conducted to evaluate the performance of the new ECG biomarkers. The first clinical trial focuses on comparing selective hERG potassium channel blockers to multichannel blockers. The goal of the second clinical trial is to evaluate if selective late sodium or L-type calcium channel blockers could reduce drug-induced QTc prolongation. Finally, data from the first clinical trial was used to study dynamic ECG biomarkers. The retrospective analysis of TQT studies showed that the most influential factors of assay sensitivity is reader variability and stability of heart rate. The latter being driven in part by study conduct. In addition, the retrospective analysis suggested that by breaking down the QTc interval into QRS, J-Tpeakc and Tpeak-Tend intervals that it is possible to detect the presence of inward current block (late sodium or L-type calcium), that can reduce the risk for TdP. In two prospective clinical studies the proposed ECG biomarkers were shown to be able to detect the presence of inward current block. Moreover, the second clinical trial showed that a selective late sodium current blocker (mexiletine or lidoacaine) shortens dofetilide-induced QTc prolongation. Lastly, using ECG measurements from periods of postural maneuvers and light exercises it was possible to detect the presence of reverse use dependence and increased instability of the QT interval (dynamic ECG biomarkers) associated with hERG potassium channel block. No changes in the dynamic ECG biomarkers was observed with ranolazine, and only small changes was observed with verapamil. Overall, the findings in this thesis show that by ensuring consistently measured QT intervals and maximizing heart rate stability the ability to detect the QTc interval prolongation associated with the positive control is improved. Ensuring consistent QT measurements also results in improved quality of QTc measurements, quantified using QTc quality metrics. In addition, the use of the J-Tpeakc and Tpeak-Tend intervals allows for discrimination between drugs that are selective hERG potassium channel blockers, and are associated with a high risk for TdP, and multichannel blockers with a low risk for TdP.