Biolin Scientific, a CiPA partner, has a long-standing interest and extensive experience in cardiac ion channels. Our instruments are used for in vitro safety screening by major pharmaceutical companies and CRO’s worldwide and we are ready to assist you in setting up your CiPA assays.
The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a proposal by the FDA, HESI, CSRC and SPS 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reports of certain drugs causing TdP and these guidelines have been successful in the respect that no drugs have been withdrawn from market for being proarrhythmic after 2005. However, the connection 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 (i.e. torsadogenic compounds prolong QTc but not all QTc prolonging drugs are torsadogenic).
The intention of the CiPA proposal is to increase the efficacy of the drug development process by 1) moving the evaluation of proarrhythmic risk to an earlier stage in the drug development process, and 2) enabling compounds with properties that today are considered as problematic to be further developed and 3) provide a stronger scientific foundation for improved future drug labeling. The CiPA proposal is based on a mechanistic understanding of proarrhythmic risk and is built around a three-component process:
- candidate drugs are tested in multiple and standardized ion channels assays using overexpressing cell lines. This proposal includes Nav5 (peak and late currents), Kv4.3 (Ito), hERG (IKr), KvLTQ1/mink (IKs) and Kir2.1 (IK1),
- 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,
- the results from the in silico simulations are verified using iPS derived cardiomyocytes
The FDA has proposed a revision of the S7B by June 2016 but there are still many questions regarding protocols, validation, translation and more that still awaits answers. and it is difficult to say when it is finally implemented.
Biolin Scientific is a CiPA partner and has a long-standing interest and extensive experience in cardiac ion channels. Our instruments are used for in vitro safety screening by major pharmaceutical companies and CRO’s worldwide and we are ready to assist you in setting up your CiPA assays.
CSRC Cardiac Safety Research Consortium
FDA Food and Drug Administration
HESI Health and Environmental Science Institute
SPS safety Pharmacology Society
TdP torsade de points
Please download our CiPA brochure CiPA Brochure.