title: Assessing the probability of drug-induced QTc-interval prolongation during clinical drug development.
abstract: 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.
authors: Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Leiden University, Leiden, The Netherlands.
authors: A S Y
authors: AS
authors: Chain
authors: K M
authors: KM
authors: Krudys
authors: M
authors: M
authors: Danhof
authors: O
authors: O
authors: Della Pasqua
mesh_terms: D000293:Adolescent; D000328:Adult; D001499:Bayes Theorem; D002940:Circadian Rhythm; D002986:Clinical Trials as Topic; D015195:Drug Design; D004335:Drug and Narcotic Control / Q000331:legislation & jurisprudence*; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D017408:Guidelines as Topic; D006339:Heart Rate; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D055815:Young Adult