![[logo] US EPA](http://www.epa.gov/epafiles/images/logo_epaseal.gif){kind=logo}
2007 CompTox Forum
Abstract - Mechanistic Cardiac Modeling and Risk Assessment
Anna Georgieva, Ruben Bibas, Antoine Soubret, Dean Bottino and Berengere Dumotier
Anna Georgieva, Ph.D. (presenting author)
Associate Director, Modeling & Simulation/Biology Biostatistics & Statistical Reporting
Novartis
One Health Plaza, East Hanover, NJ 07936-1080
Phone: 862-778-7972
E-mail: anna.georgieva@novartis.com
The last decade has been marked by the withdrawal from the market of several medicines whose use in patients has been associated with the development of torsade de pointes (TdP), a potentially life-threatening polymorphic tachycardia. In a few cases, TdP can degenerate into ventricular fibrillation and lead to sudden death, thus constituting a real problem to public heath. The recently finalized ICHS7 guideline defines the QT interval as the best biomarker for predicting the torsadogenic risk of a given compound. A growing body of evidence suggests that focusing specifically on QT interval is not always successful as drugs' torsadogenic potential is not necessarily proportional to their QT liability. It is a dynamic combination of multiple predisposing factors and components rather than a single particular event that can trigger this particular tachycardia. Pharmaceutical companies have intensively implemented methodologies to assess the possible risk of QT prolongation and TdP in humans. The main problem is determining how to best combine the capabilities of different methodologies to detect the potential of one molecular entity to induce an arrhythmia of very low clinical incidence. This talk will briefly summarize current methodologies, focusing on alternative methods to animal experimentation, especially cardiac modeling.