Metrion can offer single point and concentration-response format screening against individual cardiac ion channels or the full CiPA-compliant panel (hERG, Nav1.5, Cav1.2, KvLQT1, Kir2.1, Kv4.3); all of which have a key role in controlling the human ventricular action potential.
Our CiPA screening approach
Table of Contents
CIPA Screening Overview
The FDA and selected industry stakeholders are currently working towards launching a revised regulatory framework to assess the cardiac safety of new chemical entities. Known as the CiPA initiative, this new framework aims to improve upon the existing FDA regulations (ICH S7B and ICH E14) by introducing an updated workflow for cardiac safety assessment.
Under current guidelines, potential new therapeutics undergo initial assessment for activity against the human ether-a-go-go (hERG) ion channel, before progressing to preclinical animal models and finally a thorough QT interval study (TQT) in the clinic.
The CiPA initiative will extend the early electrophysiology-based screening to include effects on a panel of cardiac ion channels with a key role in the control of the ventricular action potential waveform. This expanded electrophysiology data will be used to create in silico modelling data to supplement data acquired from additional phenotypic assays. Such a data package should significantly improve the accuracy of identification of compounds with true cardiac liability.
For more information see www.cipaproject.org
Cardiac Ion Channel Assays
The first component of CiPA screening requires screening against an expanded panel of cardiac ion channels (hERG, Nav1.5, Cav1.2, KvLQT1, Kir2.1, Kv4.3); all of which have a key role in controlling the ventricular action potential. Metrion is a member of the HESI Cardiac Safety Committee (HTS sub team) and has developed a premium panel of six CiPA-compliant human cardiac ion channel assays using QPatch, a high fidelity, gigaseal quality automated patch clamp platform.
Our high quality automated patch clamp data can be used to drive in silico models of the human ventricular action potential and highlight potential cardiac liability at a very early stage. Metrion’s comprehensive CiPA-compliant panel offers premium data at a highly competitive price. We can offer single point and concentration-response format screening studies against individual ion channels or the full CiPA-compliant panel.
In Silico Modelling
In the second component of CiPA screening, electrophysiology data generated using the expanded panel of six ion channels is incorporated into an in silico human ventricular action potential model. Readout from the model predicts changes in the action potential duration, a surrogate marker for QT prolongation, and generation of early after depolarisations (EADs) – with appearance of EADs being highly indicative of proarrhymic liability.
Metrion has screened a small toolbox of compounds against the CiPA-complaint ion channel panel and has confirmed that the O’Hara Rudy in silico model is capable of discerning between compounds that prolong the QT interval, but are not associated with proarrhythmia (e.g. verapamil) and those that produce QT interval prolongation with an associated risk of proarrhythmia (e.g astemizole).
Translational iPSC Cardiomyocyte
The third component of CiPA confirms whether the result predicted by the in silico model translates to activity in a phenotypic assay via use of iPSC-derived cardiomyocytes. Metrion can monitor cellular excitability using the microelectrode array (MEA) technique (Maestro platform) or a dual MEA/impedance readout (CardioExcyte96). Correlating this higher throughput plate-based output with the high fidelity manual patch clamp electrophysiology data allows us to investigate compound effects on action potentials and membrane currents. Metrion has access to a variety of commercially available iPSC-derived cardiomyocyte cell lines which have been extensively validated on all phenotypic platforms available at Metrion.
Further Cardiac Safety Screening reading
Cardiac Safety Screening Resource Library
- CiPA hERG Milnes Kinetic Assay on Qpatch
- Nav1.5(late) Cardiac Safety Assay on Qpatch
- NaV1.5-ΔKPQ late INa current properties and pharmacology on the SyncroPatch 384i
- A systematic strategy for estimating hERG block potency and its implications in a new cardiac safety paradigm.
- Cross-site and cross-platform variability of automated patch clamp assessments of drug effects on human cardiac currents in recombinant cells.
- The Nav1.5 Late Current in WT and Nav1.5 ΔKPQ Mutant Channels: An Automated Patch Clamp LQT3 Electrophysiological Assay Comparison. Safety Pharmacology Society Virtual Meeting 2020.
- New CiPA Cardiac Ion Channel Cell Lines and Assays for In Vitro Proarrhythmia Risk Assessment. Japanese Safety Pharmacology Society Meeting, Tokyo, 2020
- Using new In Vitro Cardiac Ion Channel Assays and In Silico Models to Predict Proarrhythmia Risk with Automated Patch Clamp. Biophysical Society Annual Meeting, San Diego, 2020
- Development of an Impedance Based Screening Assay for Cardiac Safety and Cardiotoxicity Detection in Stem Cell derived Cardiomyocytes. Safety Pharmacology Society Annual Meeting, Barcelona, 2019
- Predicting Cardiac Proarrhythmic Risk Exclusively Using Automated Patch Clamp Data. Safety Pharmacology Society Annual Meeting, Barcelona, 2019
- New CiPA cardiac ion channel cell lines and assays for in vitro proarrhythmia risk assessment. Safety Pharmacology Society meeting, Washington DC, USA 2018.
- Assessment of human induced pluripotent stem cell-derived cardiomyocytes for evaluating drug-induced arrhythmias with multi-electrode array. Safety Pharmacology Society meeting, Washington DC, USA 2018.
- Refining in vitro QPatch cardiac ion channel QPatch and MEA iPSC cardiomyocyte assays for CiPA. SOT San Antonio 2018 poster Late Breaking 12: Safety Assessment: Pharmaceutical and Non-Pharmaceutical.
- CiPA update: Refining in vitro cardiac ion channel assays, in silico models and iPSC cardiomyocyte reagents for improved proarrhythmia risk prediction. SPS Vancouver September 2016 poster 0100.
- Human ventricular stem cell cardiomyocytes: validating in vitro assays and screening platforms for proarrhythmia risk prediction. SPS Vancouver September 2016 poster 0242.
- Human stem cell-derived cardiomyocytes: in vitro assays and screening platforms for exploring ventricular and atrial phenotypes. SPS Vancouver September 2016 poster 0247.
- Electrophysiological profiling of Axiogenesis CorV.4U iPSC-derived cardiomyocytes. Axiogenesis Workshop Cologne September 2016.
- Developing a package of in vitro human cardiac ion channel assays using automated patch clamp to predict clinical arrhythmia risk. SPS Prague September 2015.
- Presentation by Marc Rogers (Metrion CSO) at the June 2016 Sophion Ion Channel Modulation Symposium, Clare College, Cambridge (UK). CiPA update: in vitro cardiac ion channels screens, in silico models and stem cells iPS cardiomyocyte assays for pro-arrhythmia risk prediction.
- Presentation by Marc Rogers (Metrion CSO) at the September 2015 Safety Pharmacological Society, Prague. Using high quality HTS automated patch clamp data from human cardiac ion channels and in silico action potential modelling to cost-effectively predict QP prolongation and arrhythmia risk for CiPA.
Cardiac Safety Screening Technologies
- QPatch automated electrophysiology platform
- Patchliner automated electrophysiology
- Conventional manual patch clamp electrophysiology
- Plate-based impedance and microelectrode array techniques
- FlexStation plate-based imaging
Let’s work together
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