CiPA Initiative – Validation of Comprehensive In Vitro Proarrhythmia CiPA Assay
In a recent Think Tank Meeting, the FDA, the Health and Environmental Sciences Institute, and the Cardiac Safety Research Consortium (CSR) discussed the CiPA Initiative, a new paradigm to assess proarrhythmic risks. This new approach includes these components:
Mechanistic approach
The CiPA uses a mechanistic approach to evaluate proarrhythmic drugs. The tool improves drug development by identifying compounds that prolong QT intervals or may prolong QTc. The model also allows for the update of drug labels for the potential proarrhythmic risks of new drugs. CiPA aims to make these decisions easier for drug developers.
The ICH S7B/E14 approach focuses on ion channel activity in the heart. It is insufficient as a surrogate marker for proarrhythmic risk. The duration of ventricular repolarization depends on a delicate balance between inward and outward currents. When the net outward current exceeds the net inward current during the cardiac action potential plateau, the risk of proarrhythmia increases. Further, if the repolarization time is prolonged, it may produce new excitatory waveforms.
Validation
The Validation of Comprehensive In Vitro Proarcrhia Assay (CiPA) is a community-wide effort to develop a test to assess proarrhythmia risk. The proposed method combines a mechanistic approach to integrate the components of the assay. The goal is to provide the best possible proarrhythmia risk assessment. The CiPA Initiative will address these shortcomings.
The ICH S7B and E14 guidelines have prevented the introduction of many potentially torsadogenic drugs into the market, limiting research and development. The current approaches focus on QT prolongation and hERG block, but their lack of a broader range of proarrhythmic effects has limited the number of therapeutics that have reached the clinic. The Comprehensive In Vitro Proarrhythmia Assay (CiPA) seeks to provide a new paradigm for the evaluation of proarrhythmic risk and will expand the understanding of torsadogenic mechanisms beyond the hERG block.
QTc prolongation
Currently, a Comprehensive In Vitro Proarrhythmial Assay (CIPA Assay) for QTc prolongation is the most commonly used assay for QTc prolongation. QTc prolongation is a common arrhythmia, and there are several factors that can contribute to its occurrence. Hyperglycaemia has been linked to QTc prolongation in both healthy volunteers and diabetes patients. This condition is also associated with an increase in insulin levels.
The CiPA initiative also studied the impact of various drugs on QTc prolongation in iPSC-CM-derived cardiomyocytes. The iPSC-CM-based approach has demonstrated promising results for drug assessment. To develop the iPSC-CM-based assays, researchers tested 26 drugs on 2 commercially available CM cell lines using a voltage-sensitive dye. The study also used microelectrode-array and high-throughput assays to evaluate the risk of torsade de pointes. The risk of proarrhythmia increased when repolarization delayed because the inward currents weakened and new excitatory waveforms were generated.
Drugs that affect multiple ion channels
Several ion channels are critical for cardiac function. These channels are also associated with regulatory proteins. When altered, these channels delay repolarization, which can result in ventricular arrhythmias and sudden cardiac death. In addition, the QT duration correlates with the risk of ventricular tachycardia and torsade de pointes. Hence, a comprehensive analysis of QT/QTc is necessary for evaluating drug-induced cardiac side effects.
To assess drug safety, the Ion Channel Working Group has developed an improved model for the Comprehensive In Vitro ProarrhythmiAssay for drugs that affect multiple ion-channels. This model extends the traditional IC50 prediction model by taking into account multiple ion channels. The model is based on data from in vitro studies of seven major ion currents and yields the qNet metric.
Human-based studies of proarrhythmic risk
The CiPA Assay is a proposed method to evaluate proarrhythmic risk in human-based studies. The consortium, led the Health and Environmental Sciences Institute as well as the FDA, will provide guidance and expertise to various working groups and ensure the safety and efficacy of proarrhythmic drugs.
The ICH S7B/E14 approach to measuring the ventricular repolarization time is inherently limited, as it measures only one ion channel. As a surrogate marker of proarrhythmic risk, the QTc interval is unsuitable. A fine balance between inward and outward currents determines the duration of ventricular repolarization, and if repolarization is delayed, new excitatory waveforms may form.
