Rechanneling the cardiac proarrhythmia safety paradigm: A meeting report from the Cardiac Safety Research Consortium

Abstract

This white paper provides a summary of a scientific proposal presented at a Cardiac Safety Research Consortium/Health and Environmental Sciences Institute/Food and Drug Administration-sponsored Think Tank, held at Food and Drug Administration's White Oak facilities, Silver Spring, MD, on July 23, 2013, with the intention of moving toward consensus on defining a new paradigm in the field of cardiac safety in which proarrhythmic risk would be primarily assessed using nonclinical in vitro human models based on solid mechanistic considerations of torsades de pointes proarrhythmia. This new paradigm would shift the emphasis from the present approach that strongly relies on QTc prolongation (a surrogate marker of proarrhythmia) and could obviate the clinical Thorough QT study during later drug development. These discussions represent current thinking and suggestions for furthering our knowledge and understanding of the public health case for adopting a new, integrated nonclinical in vitro/in silico paradigm, the Comprehensive In Vitro Proarrhythmia Assay, for the assessment of a candidate drug's proarrhythmic liability, and for developing a public-private collaborative program to characterize the data content, quality, and approaches required to assess proarrhythmic risk in the absence of a Thorough QT study. This paper seeks to encourage multistakeholder input regarding this initiative and does not represent regulatory guidance.

Cardiac ion channels

“…CiPA consists of 3 components: in vitro characterization of electrophysiological effects on 7 cardiac ion channels expressed recombinantly, in silico modeling of the impact on the human ventricular action potential, and characterization of electrophysiological effects on human stem cell-derived cardiomyocytes using multi-electrode arrays and voltage-sensitive dye. 94 Expert working groups are tasked with developing and testing detailed protocols for each of the 3 components, which will be validated by testing 29 established drugs spanning the range from low to high proarrhythmic liability. 95,96 Once established, CiPA may remove the need for expensive Thorough QT studies for most drug candidates.…”

Accurate nanoelectrode recording of human pluripotent stem cell-derived cardiomyocytes for assaying drugs and modeling disease

“…This measurement could yield the information relevant to pre-clinically monitor drug cardiotoxicity 3 , track cardiomyocyte maturation, and perform any variety of experiments enabled by multi-day current clamp-like measurements. In all these examples, it is vital to benchmark nanopillars against existing technology.…”

“…From repairing damaged tissue in vivo to predicting drug efficacy, human pluripotent stem cells (hPSCs) have become a promising solution to many bottlenecks in human biological research [1][2][3][4][5][6] . There have been many efforts to generate cardiomyocytes (CMs) derived from human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) due to the difficulty in obtaining human cardiac tissue by other methods 7 .…”

Human pluripotent stem cell-derived cardiomyocyte based models for cardiotoxicity and drug discovery

“…However, there are two caveats to these studies, both of which have functional consequences: (i) the hPSC-CM phenotype was fetal-like [12] and (ii) the highly oriented cytoarchitecture -CM alignment and intercellular interactions -of the native myocardium was not recapitulated [13].…”