Mind the gap : predicting cardiovascular risk during drug development

Abstract

Cardiovascular safety issues, specifically drug-induced QT/QTc-interval prolongation, remain a major cause of drug attrition during clinical development and is one of the main causes for post-market drug withdrawals accounting for 15-34% of all drug discontinuation. Given the potentially fatal consequences of this concentration-dependent adverse drug reaction, regulatory authorities have reacted to this __pharmacoepidemic__ by denying or delaying the approval of a number of new drugs and placing severe restrictions on the use of many old and some new drugs because of concerns arising from their propensity to prolong the QT/QTc-interval. The thorough-QT trial, introduced in ICH E14 guideline, has also been mandated as part of all new drug applications. Currently, a multitude of safety trials are performed in different phases of the drug development process. Despite numerous efforts to improve the detection of QT/QTc-prolonging effects, many limitations still exist today. In this thesis, an overview of the concepts, underlying physiological and methodological aspects pertinent to the evaluation of chronotropic effects, as well as the clinical relevance of the use of prolonged QTc-intervals as a biomarker of cardiac-toxicity are explored. Novel tools and approaches for assessing the prolongation of QTc-interval, translating findings from clinical trials to real life scenarios are presented.