Metrion Biosciences Cardiac Safety Screening Services
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CiPA Screening

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

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Metrion offer high fidelity manual and automated patch clamp assays that deliver high quality cardiac safety data for all of the human cardiac ion channels known to contribute to pro-arrythmia clinical risk.

CiPA Overview

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The Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative was launched by the FDA in July 2013
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.

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Figure 1a. hERG traces
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Figure 1b. Nav1.5 traces
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Figure 1c. Cav1.2 traces
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Figure 1d.KvLQT1 traces
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Figure 1e. Kir2.1 traces
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Figure 1f. Kv4.3 traces

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).

In silico traces astemizole and verapamilv2
Figure 2. CiPA Screening – In Silico modelling

Translational iPSC Cardiomyocyte 
Assays

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.

Maestro heatmap
Figure 3. iPSC cardiomyocyte assays – Maestro MEA heatmap of cardiac excitability

Read next More on Cardiac Translational Assays

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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
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What are your specific ion channel and assay needs?

If you have any questions or would like to discuss your specific assay requirements, we will put you directly in touch with a member of our scientific team. Contact us today to discover more.