At the Society of Toxicology 58th Annual Meeting and ToxExpo from March 10th to 14th at the Baltimore Convention Center, poster presentation by Richard Printemps of PhysioStim on Tuesday March 12th 3:00pm – 4:30pm Poster Board P463 Convention Center Exhibition Hall. 

Incorporating the CiPA Paradigm into an Integrated Cardiac Risk Assessment.

Authors:  M. Morton1, R. Printemps2, M. Le Grand2, M. Davies3, and R. Roberts1.

1ApconiX Ltd, Alderley Park, United Kingdom; 2PhysioStim, Toulouse, France; and 3QT Informatics Ltd., Alderley Park, United Kingdom.

Abstract:

Safety-related attrition remains a major issue in drug discovery and development with cardiovascular toxicity accounting for around 20% of both preclinical and clinical failures. Currently, compounds are tested for inhibition of the hERG potassium channel since this is associated with QT interval prolongation and a life-threatening cardiac arrhythmia (Torsades de Pointes). The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative proposes more thorough investigation of cardiac electrophysiology preclinically, by (1) testing at additional ion channel targets, (2) in silico modelling of ion channel data to predict effects on cardiac action potential (AP) and (3) verification of the observed effects in human stem cell-derived cardiomyocytes. The aim of this work was to assess how data generated under this CiPA paradigm fits into integrated cardiac risk assessment. The activity of a panel of compounds of was tested against 7 cardiac ion channels (hERG, hNaV1.5 peak and late current, hCaV1.2, hKir2.1, hKvLQT1 and Kv4.3) which were stably expressed in recombinant cell lines. Ion currents were measured by automated patch-clamp (PatchLiner, Nanion Technologies). The resulting IC50, % inhibition and Hill Coefficients were used as inputs for the in silico Action Potential (isAP) model to simulate AP amplitude, Vmax (maximum rate of depolarisation) and APD90 in virtual cardiomyocytes. Impedance and field potential measurements were made using human induced pluripotent stem cell (hiPSC) Cardiomyocytes (Ncardia) on the xCELLigence CardioECR (ACEA) platform. Compounds tested had varying degrees of ion channel activity ranging from inhibition of a single channel to activity at many. In silico, using the isAP model predicted changes in action potential durations and Vmax including representation of subject-to-subject variability. Both field potential and impedance metrics from hiPSC derived cardiomyocytes yielded data describing the varied effects of compounds on cardiomyocytes. By deploying ion channel profiling, in silico modelling and field potential measurements in vitro, compounds can be classified with different degrees of proarrhythmic risk (low, medium or high). This provides critical information to the project on risks associated with progressing into in vivo studies and ultimately into the clinic.

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The European Centre of Excellence for nonclinical cardiovascular electrophysiology is an alliance of ApconiX and PhysioStim.  Read more here.