title: CiPA: Ongoing testing, future qualification procedures, and pending issues.
abstract: BACKGROUND
  The comprehensive in vitro proarrhythmia assay (CiPA) is a nonclinical, mechanism-based paradigm for assessing drug proarrhythmic liability.
  The first CiPA assay determines effects on cloned human cardiac ion channels. The second investigates whether the latter study-generated metrics engender proarrhythmic markers on a computationally reconstructed human ventricular action potential. The third evaluates conclusions from, and searches possibly missed effects by in silico analysis, in human stem cell-derived cardiomyocytes (hSC-CMs). CiPA ad hoc Expert-Working Groups have proposed patch clamp protocols for seven cardiac ion channels, a modified O'Hara-Rudy model for in silico analysis, detailed procedures for field (MEA) and action potential (VSD) measurements in hSC-CMs, and 29 reference drugs for CiPA assay testing and validation.
  
  
  CONCLUSIONS
  CiPA adoption as drug development tool for identifying electrophysiological mechanisms conferring proarrhythmic liability to candidate drugs is a complex, multi-functional task requiring significant time, reflection, and efforts to be fully achieved.
authors.affiliation: 54 Rue de la Glacière, 75013 Paris, France. Electronic address: iciliocavero@aol.com.
authors.forename: Icilio
authors.initials: I
authors.lastname: Cavero
authors.affiliation: 13765 Seabiscuit Drive, Reno, NV, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Holzgrefe
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D001681:Biological Assay / Q000379:methods* / Q000592:standards / Q000639:trends; D002460:Cell Line; D004353:Drug Evaluation, Preclinical / Q000379:methods* / Q000592:standards / Q000639:trends; D015507:Drugs, Investigational / Q000009:adverse effects*; D017408:Guidelines as Topic / Q000592:standards; D006801:Humans; D007473:Ion Channels / Q000378:metabolism; D007564:Japan; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects; D015203:Reproducibility of Results; D013234:Stem Cells / Q000187:drug effects; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D015507:Drugs, Investigational; D007473:Ion Channels
keywords: Cardiac action potential; Cardiac ion channel assays; CiPA; CiPA working groups; Comprehensive in vitro proarrhythmia assay; Human stem cell-derived cardiomyocytes; MEA; Safety Pharmacology; VSO; hSC-CMs