In evaluation of cardiac toxicity of drug candidates, many drugs with effects on hERG and QTc prolongation but little actual Torsades de pointes (TdP) risk are deprioritized or excluded from further development or, if approved, see their clinical use limited by inappropriate warnings in product labeling.
Here at Acroscell, we provide our clients with a comprehensive pack of CiPA evaluation service.
Fig. 1 Effect of predominant hERG potassium channel block vs. balanced ion channel block on QT prolongation and generation of torsade de pointes
The duration of ventricular repolarization is determined by a fine balance between inward (depolarizing) and outward (repolarization currents) that are activated with each heartbeat. Drugs that affect both inward and outward cardiac currents (e.g. verapamil, ranolazine) may therefore have effects on repolarization and the QTc interval, but not be associated with the generation of TdP due to the blockade of inward currents.
The Comprehensive In Vitro Pro-Arrhythmia Assay (CiPA) represents a paradigm shift towards a more complete assessment of proarrhythmic risk rather than QT prolongation alone. CiPA is a novel cardiac safety screening proposal that evaluates drug effects on each cardiac ion channel type individually (high-throughput), predicts net effect on the cardiomyocyte action potential with computer modeling, and then verifies the in silico conclusions using human stem cell-derived cardiomyocytes.
Automated electrophysiology screening against an expanded panel of six cardiac ion channels, including hERG.
In silico modelling using electrophysiology data from the expanded ion channel panel.
Confirmation of in silico predictions using translational assays employing human iPSC-derived cardiomyocytes.
Fig. 2 The CiPA Workflow
If you have any special needs in our CiPA Service, please contact us at Email or Telephone for this special service. Let us know what you need and we will accommodate you. We look forward to working with you in the future.
Vicente J, et al. Mechanistic Model-Informed Proarrhythmic Risk Assessment of Drugs: Review of the ‘CiPA’ Initiative and Design of a Prospective Clinical Validation Study. Clin Pharmacol Ther. 2018; 103: 54–66.
Sager PT., et al. Rechanneling the cardiac proarrhythmia safety paradigm: a meeting report from the Cardiac Safety Research Consortium. Am. Heart J. 2014; 167: 292–300.