CiPA – Comprehensive In Vitro Proarrhythmia Assay
The objective of the Comprehensive in vitro Proarrhythmia Assay (CiPA) consortium, headed by US FDA and HESI, is to engineer an assay for assessment of the pro-arrhythmic potential of new drugs with improved specificity compared with the current hERG assay.
The intention of the CiPA proposal is to increase the efficacy of the drug development process by
- moving the evaluation of proarrhythmic risk to an earlier stage in the drug development process
- enabling compounds with properties that today are considered as problematic to be further developed
- providing a stronger scientific foundation for improved future drug labelling.
Sophion and CiPA
Sophion Bioscience is a CiPA partner with long-standing interest and extensive experience in cardiac ion channels and cardiac safety assays.
QPatch has been used for in vitro safety screening by major pharmaceutical companies since 2005 and many researchers regard the Sophion QPatch series as the benchmark APC solution for cardiac safety. In recent years we have also seen an increasing interest in running cardiac safety assays in unattended HTS format on Qube 384. We, as well as CRO’s worldwide, are ready to assist you in setting up your CiPA assays.
Cardiac ion channel assays
All standard CiPA recommended assays are available on QPatch and Qube 384. Please ask your application scientist for help to set them up if they are not already installed.
Also, the challenging hERG kinetic Milnes protocol is available. This assay is recommended by the CiPA committee since it can detect changes in hERG amplitude and decay kinetics due to drug binding and trapping. The Milnes protocol can easily be run on QPatch and the assay meets the FDA’s CiPA requirements for improved arrhythmia prediction. Data has a very good correlation with FDA’s manual patch clamp data. Read the application report here.
Sophion CiPA publications and videos
- Paper: A systematic strategy for estimating hERG block potency and its implications in a new cardiac safety paradigm
- Paper: Cross-site and cross-platform variability of automated patch clamp assessments of drug effects on human cardiac currents in recombinant cells
- See other publications related to Cardiac Ion Channels done on QPatch and Qube here.
- You can also watch presentations by Clint Young (Xenon) and Lazlo Urban (Novartis) from one of our SPS seminars.
- Or view Marc Rogers’ (Metrion Bioscience) take on CiPA or Arthur ‘Buzz’ Brown (MemChan Pharma) presentation on Predicting in vivo safety from in vitro tests from Sophions Ion Channel Modulation Symposium
More about CiPA
The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a proposal by the FDA (Food and Drug Administration), the HESI (Health and Environmental Science Institute), the CSRC (Cardiac Safety Research Consortium) and the SPS (Safety Pharmacology Society) which is ultimately aimed at revising the non-clinical ICH-S7B and replacing the clinical ICH-E14 guidelines. The S7B and E14 guidelines were implemented 2005 in response to reports of certain drugs causing TdP (torsade de points) and these guidelines have been successful in that no drugs have been withdrawn from the market for being proarrhythmic since 2005. However, the link between proarrhythmia and QTc prolongation is complex and depends on several other factors in addition to drugs blocking the hERG channel and while QTc prolongation is a sensitive marker for proarrhythmia it is also moderately specific because torsadogenic compounds prolong QTc, but not all QTc prolonging drugs are torsadogenic.
The CiPA proposal is based on a mechanistic understanding of proarrhythmic risk and is built around a three-component process:
1. candidate drugs are tested in multiple and standardized ion channels assays using overexpressing cell lines. This proposal includes NaV1.5 (peak and late currents), Kv4.3 (Ito), hERG (IKr), KvLTQ1/mink (IKs) and Kir2.1 (IK1),
2. the data from the ion channel assays are used in a computational model of a cardiomyocyte action potential model to see if the compound yields proarrhythmic markers. This model is calibrated using data from well-characterized reference compounds,
3. the results from the in silico simulations are verified using iPS derived cardiomyocytes
The FDA has proposed a revision of the S7B in 2016 but there are still many questions regarding protocols, validation, translation and more still awaiting answers. It is difficult to say when the revision will be finally implemented.
Read about the CiPA consortium here.