Model-Based Correction to the QT Interval for Heart Rate for Assessing Mean QT Interval Change Due to Drug Effect

摘要

Dmgs that alter ventricular repolarization have been associated with malignant ventricular arrhythmia, which has been shown to increase with increasing QT interval-the time required for ventricular depolarization and repolarization. To determine whether a new drug, especially a nonanti-arrhythmia dmg, can cause an increase in the QT interval is a necessary step in safety evaluation. Since the QT interval is inversely related to the heart rate, this relationship needs to be accounted for in the assessment of drug effect. In current practice, the most commonly-used approach for assessing mean change in the QT interval is to coned the QT interval by one of many competing correction methods to QT_C, then to conduct statistical analysis on QT_C, a disjoint two-step approach. The shortcomings of such an approach are: 1. The conection formulas often fail to correct the QT interval for the change in heart rate and this can lead to biased estimation of the dmg effect; and 2. The analysis based on QT_C only provides estimation of the drug effect at a fixed heart rate (60 bpm), which ignores potential interaction between the dmg effect on the QT interval and the heart rate.