CiPA hERG Milnes kinetic assay on QPatch
Cardiac safety side-effects remain the leading cause of new compound attrition during the drug discovery process (Valentin and Redfern, 2017), suggesting that more robust preclinical in vitro, ex vivo and in vivo assays and models are required to predict human clinical risk. Currently, the industry is moving away from an over-reliance on the human Ether-a-go-go related potassium channel (hERG, KV11.1) assay and QT prolongation readouts by developing new initiatives that provide a more balanced assessment of patient risk, focusing in particular on cardiac arrhythmia liability. The FDA’s Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative and Japanese regulatory authorities (JiCSA, CSAHi) aim to more accurately model and predict arrhythmia risk by including additional human cardiac ion channels in patch clamp electrophysiology screening panels. This broader dataset is then used in sophisticated in silico models of the human ventricular action potential to predict arrhythmias. After 5 years of extensive collaborative effort by working groups in the UK, EU, US and Japan, it has become apparent that incorporating data obtained from the ‘big 6’ panel of cardiac ion channel assays (hERG, NaV1.5, CaV1.2, KVLQT1, KV4.3, and Kir2.1) into standard in silico action potential models allows the accurate prediction of proarrhythmic liability of most, but not all, clinical drugs with well characterised risk profiles.