CiPA (Comprehensive In Vitro Pro-Arrhythmia Assay) is a scientific CSRC/HESI/FDA/SPS-sponsored proposal that aims to define a novel integrated preclinical in vitro/in silico paradigm in which the proarrhythmic potential of new drugs would be primarily assessed using nonclinical in vitro human models, based on solid mechanistic considerations of torsades de pointes proarrhythmia. This CiPA paradigm would shift the emphasis from the present approach that strongly relies on prolongation of the corrected QT interval (QTc) as a surrogate marker of proarrhythmia, and could obviate the need for clinical thorough QT (TQT) studies performed during the later phases of drug development.
Several work streams have been established in support this new paradigm. In view of the central role of ion channel data in validating the CiPA paradigm, and the significant level of experience and expertise within the Safety Pharmacology Society (SPS), the SPS Board of Directors endorsed the formation of an Ion Channel Working Group (ICWG). This ICWG, chaired by Bernard Fermini (Pfizer) and Najah Abi-Gerges (AstraZeneca), is tasked of bringing together expertise and resources required to deliver best practice recommendations for generating the ion channel data needed for in silico cardiac action potential (AP) simulations of proarrhythmic liabilities.
Since its launch in January 2014, the ICWG has been actively working to address important questions related to best practices including:
1) Which ion channels should be selected to support in silico AP modelling, and what properties should be studied (IC50 determinations, kinetics, rate/use/voltage dependence, etc.?)
2) What requirements are needed to deliver robust, reliable and reproducible ion channel data in a high throughput screening (HTS) environment in support of in silico modelling?
As a first step, a survey was sent out to active SPS members with the purpose of collecting frequency/type data on the commonly used ion channels in the various laboratories, in order to gather qualitative information on their relevance to drug-induced cardiac safety concerns, and proarrhythmia. Results from this survey were used to identify 7 ion channels of interest (IKr, IKs, Ito, IK1, ICa and INa (peak and late)) and guide the development of recommended protocols in an effort to generate data to be used for in silico AP simulations. These protocols focus not only on defining potency but also address potential effects on kinetics and state dependency, while being practical and amenable to HTS. Preliminary data have been generated for a few key channels, and are currently being shared with the in silico group with the expectation that a number of iterations may be required initially to define the most valuable inputs required to evaluate the proarrhythmic potential of new drugs. The ICWG is looking forward to the next steps of integrating and interpreting ion channel and in silico data, in an effort to fully validate the CiPA paradigm.
Additional information on the work of the ICWG in support of CiPA will be presented at the annual SPS meeting on October 22nd, 2014 (Plenary: Update and Perspectives on CiPA), and the CSRC/HESI/FDA/SPS CIPA Update Workshop on December 11th, 2014.
ICWG 2014 Membership
Najah Abi-Gerges AstraZeneca (co-chair)
Khuram Chaudray GSK
Tom Colatsky U.S. FDA
William Crumb Zenas Technologies
Bruce Damiano Janssen
Gul Erdemli Novartis
Bernard Fermini Pfizer Inc (co-chair)
Gary Gintant AbbVie
Jules C. Hancox Bristol University
John Imredy Merck
John Koerner U.S. FDA
Jim Kramer Chantest
Paul Levesque BMS
Zhihua Li U.S. FDA
Anders Lindqvist Sophion
Stanley Nattel Montreal Heart Institute
Carlos Obejero-Paz Chantest
David Rampe Sanofi
Gail Robertson Wisconsin University
Kowei Sawada Eisai
David Strauss U.S. FDA
Jamie Vandenberg Victor Chang Cardiac Research Institute