Drug-induced QT interval prolongation and Torsades de Pointes (TdP) arrhythmia are the leading causes for drug withdrawal from market. For the past decade, in vitro hERG channel assays and in vivo QT measurements have been conducted as surrogate biomarkers for proarrhythmic risk propensity according to ICH S7B and ICH E14 guidelines. This standard, although effective, suffers from lack of specificity and has led to unnecessary compound attrition during drug development.
The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative, a partnership between Food and Drug Administration (FDA) and several agencies and consortia, including Health Canada, the European Medicines Agency, and Japan’s National Institute of Health Sciences, is an effort to overcome limitations of the current assessment model. The aim of the CiPA initiative is to facilitate the adoption of a new paradigm for assessment of the clinical potential of TdP that is not measured exclusively by the potency of hERG block and not at all by QT prolongation. Four work streams that focus on each component of the project, 1) ion channel, 2) in silico, 3) myocyte and 4) early phase human ECG, have been established.
Eurofins Discovery has worked with the CiPA consortium to validate the following Ion Channel currents- rapid inward sodium current (INa), late sodium current (INaL agonist or antagonist), L-type calcium channel (ICaL), multiple outward potassium currents comprising the transient outward current (Ito), the slow (IKs) and rapid (IKr) components of the delayed rectifier potassium channels, and the inward rectifier channel (IK1) – using HESI-sponsored High Throughput Screening (HTS) cardiac protocols in a QPatch HT system.
Eurofins Discovery also used human induced pluripotent stem cell derived ventricular cardiomyocytes to offer an integrated system to study drug impact on cardiomyocyte function. Stem cell myocytes present an opportunity to move beyond single-component analysis into a rich, dynamic system and thus provide a more appropriate preclinical model for cardiac liability assessment. We measured field potential duration (FPD) using Axion BioSystems Multi Electrode Array (MEA) as well as calcium transient using FLIPR of well characterized drugs and assessed their cardiac safety liability.
- Limitations of current ICH S7B hERG centric strategy
- Needs for the Comprehensive In Vitro Proarrhythmia Assay (CiPA) and introduction to CiPA
- Eurofins Discovery’s contribution to the CiPA initiative and development of multi ion channel CiPA panels and cardiomyocyte assays for cardiac liability assessment
- How Eurofins Discovery developed highly robust and precise assays to fulfill future regulatory guidelines
Muthukrishnan Renganathan, PhD
Ph.D. Madurai Kamaraj University, Madurai, India, Senior Scientist , Ion Channels Group, Eurofins Discovery, St. Charles, MO
Cost: No Cost!