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Invited Talk

Drug arrhythmogenicity and preclinical cardiac safety evaluation:
are we able to run over the main hurdles?

Dr. Bérengère Dumotier
Preclinical Cardiosafety Expert, Senior Investigator
NOVARTIS Institutes for Biomedical Research, Basel

Abstract

Cardiotoxicity is one of the major forms of drug toxicity and accounts for most recalls, delays in drug approvals, or non approvals. One of the biggest challenges is how to predict cardiac risk early and accurately in the drug development process. In preclinical cardiac safety pharmacology, one of the important questions is how to best combine the different methodologies with their respective strengths and limitations to reliably detect and quantify the arrhythmogenic potential of non cardiovascular drugs in man. In the special case of polymorphic ventricular tachycardia, Torsades de Pointes (ICHS7B), it is a more a question of dynamic combination of multiple factors and components rather than a single particular event that predisposes to this kind of potentially lethal cardiac arrhythmia. The preclinical assays in place for evaluating cardiac electrophysiological effects of a given drug including the use of cardiac cells, tissues and whole heart systems, must be highly reliable, highly specific and reproducible.

This presentation will focus on:
- The preclinical core battery assays (“the basic hurdle mechanics”).
- What do we lose or gain in translation to patients? (“the take off / landing technics”)
- Identifying gaps and found appropriate solutions (“how to clear the hurdle properly”)
- Promising approaches, new technologies (“our eyes on the next hurdle”)

Biography

Bérengère Dumotier completed her PhD in Cardiac Electrophysiology in 1999 at the University Hospital in Lille,France (CHU, laboratory of Pharmacology; Pr. B. Dupuis). She was hired in Novartis in 1999 to establish an in vitro cardiac safety laboratory in Preclinical Safety Department. She is currently leading a research program focusing on electrophysiological signature for torsadogenic drugs. Since 2005, she is a preclinical cardio-safety expert responsible for supporting preclinical programs via (i) the global assessment of the preclinical cardiosafety data within the Discovery Cardiac Advisory Team and (ii) a project team membership. She gives expert statements to global project teams and the integrated Safety Assessment group with regard to cardiac safety issues from compound selection point to proof of concept in man. She is a core member of the Safety Pharmacology Steering Committee and of the Clinical Cardiovascular Advisory board. She also contributes to the global co-ordination of the cardiosafety pharmacology activities in Novartis. Additionally, she participates to the development of a computerized based system of heart model and leading the development of an automatic analyzing software of electrophysiological data.
 

Volker Koch, 08/2010