Assessing the Probability of Drug-Induced QTc-Interval Prolongation During clinical Drug

early in the course of clinical development of new non-antiarrhythmic drugs, it is important to assess the propensity of these drugs to prolong the QT/QTc-interval. The current regulatory guidelines suggest using the largest time-matched mean difference between drug and placebo (baseline-adjusted) groups over the sampling interval, thereby neglecting any potential exposure–effect relationship and nonlinearity in the underlying physiological fluctuation in QT values. Thus far, most of the attempted models for characterizing drug-induced QTc-interval prolongation have disregarded the possibility of model parameterization in terms of drug-specific and system-specific properties. u sing a database consisting of three compounds with known dromotropic activity, we built a Bayesian hierarchical pharmacodynamic ( p D) model to describe QT interval, encompassing an individual correction factor for heart rate, an oscillatory component describing the circadian variation, and a truncated maximum-effect model to account for drug effect. The explicit description of the exposure– effect relationship, incorporating various sources of variability, offers advantages over the standard regulatory approach.