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Assessing the probability of drug-induced QTc-interval prolongation during clinical drug development.

Chain, ASY; Krudys, KM; Danhof, M; Della Pasqua, O; (2011) Assessing the probability of drug-induced QTc-interval prolongation during clinical drug development. Clin Pharmacol Ther , 90 (6) pp. 867-875. 10.1038/clpt.2011.202.

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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.

Type: Article
Title: Assessing the probability of drug-induced QTc-interval prolongation during clinical drug development.
Location: United States
DOI: 10.1038/clpt.2011.202
Keywords: Adolescent, Adult, Bayes Theorem, Circadian Rhythm, Clinical Trials as Topic, Drug Design, Drug and Narcotic Control, Drug-Related Side Effects and Adverse Reactions, Female, Guidelines as Topic, Heart Rate, Humans, Long QT Syndrome, Male, Middle Aged, Models, Biological, Young Adult
UCL classification: UCL > School of Life and Medical Sciences
UCL > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology
URI: http://discovery.ucl.ac.uk/id/eprint/1400975
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