The Safety Pharmacology Society is pleased to invite you to a webinar on Comprehensive In Vitro Proarrhythmia Assay (CiPA): An Update from An Industry Perspective on April 16, at 11:00 am EDT.
Title: Defining the CiPA Paradigm: An Update from the Ion Channel Working Group (ICWG)
Presenter: Bernard Fermini, PhD, Ion Channel Discipline Lead Global Safety Pharmacology, Pfizer
Summary: The Ion Channel Working Group (ICWG) is tasked of bringing together expertise and resources required to deliver best practice recommendations for generating ion channel data needed to optimize the output of the in silico human cardiac AP simulations. One of its initial decisions has been the selection of seven human ion channels as study target for the CiPA paradigm. Protocols have been defined for each of the channels, and ongoing studies using reference drugs, like dofetilide, cisapride and verapamil, are being used to parametrize / train the in silico model. The goal is to define, standardize, and retain protocols that will deliver the most relevant information, using plate-based electrophysiology platforms, to detect the proarrhythmic potential of new drugs.
Title: Successes and Evolving Challenges Posed by the Comprehensive In Vitro Proarrhythmia Assay (CiPA) Initiative
Presenter: Gary Gintant, PhD, AbbVie for the CiPA Working Groups
Summary: Delayed ventricular repolarization (manifest as QT prolongation on the ECG) is a surrogate marker for Torsades-de-Pointes (TdP) proarrhythmia, and many drugs that delay repolarization reduce iKr (hERG) current through the Kv11.1 potassium channel encoded by the KCNH2 gene. Preclinical and clinical strategies to detect such effects have effectively prevented compounds from further development (and thus prevented the withdrawal of newly marketed drugs). This success has come with an additional cost of removal of novel drug candidates from the drug pipeline, as a) block of iKr current can be a gross oversimplification of a drug’s effect on repolarization, and b) delayed repolarization-QT prolongation in preclinical models need not reflect clinical responses. The goal of the Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative is to provide a more robust early preclinical assessment of proarrhythmic risk of evolving drug compounds, thus minimizing the necessity of a thorough QT study (mandated by the ICH E14 guidance) to detect clinical QTc prolongation (a surrogate marker of proarrhythmia). This goal will be accomplished by integrating a) effects of drugs on human cardiac ionic currents in heterologous expression systems, b) in silico reconstructions of human ventricular electrophysiologic responses linked to proarrhythmia, and c) confirmation of effects on ionic currents/ventricular electrical activity using human induced pluripotent stem-cell derived cardiomyocytes (hiPSC-CM’s). This presentation will discuss progress made within the mechanistic CiPA paradigm, including the role of hiPSC-CM’s in the overall integrated assessment of proarrhythmic risk. The goals and preliminary results from a pilot study with hiPSC-CM’s using microelectrode array and voltage-sensitive optical approaches will be discussed.
Title: Implementation of CiPA During Drug Development: Practical Considerations
Presenter: Hugo Vargas, PhD, DSP, Scientific Director, Toxicology Sciences, Amgen
Summary: This overview will describe some nonclinical-clinical datasets of agents developed according to current S7B guidance, and practical issues to consider when thinking about the use of CiPA assays for proarrhythmia risk assessment.
Moderator: Simon Authier, DVM, MBA, PhD, DSP, Director Safety Pharmacology, CiToxLAB
We look forward to your participation.
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