Comprehensive in vitro Proarrhythmia Assay, a novel in vitro/in silico paradigm to detect ventricular proarrhythmic liability: a visionary 21st century initiative.

INTRODUCTION

The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a novel safety screening proposal intended to replace the 2005 regulatory strategy recommended by the International Conference of Harmonization S7B guideline.

AREAS COVERED

CiPA consists of three components. The first assay evaluates candidate drug effects on key cardiac ion channels. Then, simulations test whether the channel dataset yields proarrhythmic markers on a computationally reconstructed human ventricular cardiomyocyte action potential. Finally, the relevance of in silico conclusions is verified by determining the electrical activity of human stem cell-derived ventricular cardiomyocytes.

EXPERT OPINION

The CiPA initiative is intended to move safety pharmacology from a predominantly traditional pharmacodynamics approach to in silico and in vitro drug toxicity assessment. In practice, CiPA assays will have to be compliant with regulatory safety pharmacology tenets. The latter will necessitate international consensus on assay protocols, method standardization and validation and, thus, is likely to involve protracted discussions to achieve agreement. As such, full CiPA implementation by July 2015, as currently envisaged, to supplant E14 guidance for a thorough QT/QTc interval study as prerequisite for noncardiac drug marketing approval, appears to be difficult. Nevertheless, safety stakeholders should do their best to validate and implement the CiPA initiative in the shortest possible time.