Predicting Cardiac Proarrhythmic Risk Exclusively Using Automated Patch Clamp Data

著者: Edward SA Humphries, John Ridley, Robert Kirby and Marc Rogers

Recent work by FDA and HESI CiPA working groups indicate that in vitro hERG, Nav1.5 and Cav1.2 potency data in addition to dynamic hERG kinetic data is required to accurately predict proarrhythmic risk. Below we explore two key challenges in exclusively using automated patch clamp for risk prediction:

  1. Metrion has previously shown the ability to implement the difficult Milnes protocol on QPatch but the challenges of producing full concentration-response formats required for in silico models are unknown
  2. Cav1.2 inhibition values for compounds such as verapamil have been
    variable, with literature IC50 values >10 µM compared to the 202 nM IC50 obtained by manual patch clamp in the original CiPA study. The similar potency of verapamil against Cav1.2 and hERG make it a Multiple Ion Channel Effect (MICE) compound and “rescues” it from being classed as a high-risk proarrhythmia compound as shown by Li et al.
  3. QPatch dynamic hERG and Cav1.2 data from multiple voltage protocols
    were used to assess proarrhythmic risk using the FDA’s in silico model.