Assessing the Probability of Drug-Induced QTc-Interval Prolongation During Clinical Drug Development

作者：Chain A S Y; Krudys K M; Danhof M; Della Pasqua O^*

来源：Clinical Pharmacology & Therapeutics, 2011, 90(6): 867-875.

DOI：10.1038/clpt.2011.202

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. Using a database consisting of three compounds with known dromotropic activity, we built a Bayesian hierarchical pharmacodynamic (PD) 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.

• 出版日期2011-12