CiPA: Ongoing testing, future qualification procedures, and pending issues

• Published in: Journal of pharmacological and toxicological methods Vol. 76; pp. 27 - 37
• Main Authors: Cavero, Icilio, Holzgrefe, Henry
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2015
• Subjects: Action Potentials - drug effects; Arrhythmias, Cardiac - chemically induced; Biological Assay - methods; Biological Assay - standards; Biological Assay - trends; Cardiac action potential; Cardiac ion channel assays; Cell Line; CiPA; CiPA working groups; Comprehensive in vitro proarrhythmia assay; Drug Evaluation, Preclinical - methods; Drug Evaluation, Preclinical - standards; Drug Evaluation, Preclinical - trends; Drugs, Investigational - adverse effects; Guidelines as Topic - standards; hSC-CMs; Human stem cell-derived cardiomyocytes; Humans; Ion Channels - metabolism; Japan; MEA; Myocardium - metabolism; Myocytes, Cardiac - drug effects; Reproducibility of Results; Safety Pharmacology; Stem Cells - drug effects; United States; United States Food and Drug Administration; VSO; United States; Japan; Ito; Ca50; ICaL; CDI; Ca90; GLP; IKs; IKr; Cardiac ion channel assays; IC50; Safety Pharmacology; ILSI; CTWG; QTc; VSD; MEA; EAD; VSDI; AP; HESI; VSO; FPA; hSC-CM; FPD; TdP; FDA; HTP; INaF; ICWG; Human stem cell-derived cardiomyocytes; FP; BP; IK1; BR; WG; CDER; FAERS; INaL; DDT; CiPA working groups; CiPA; hSC-CMs; MWG; DAD; ECG; APD50; Cardiac action potential; Comprehensive in vitro proarrhythmia assay; ICH; APD; APD90; TQT; AERS
• ISSN: 1056-8719; 1873-488X
• DOI: 10.1016/j.vascn.2015.06.004

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. 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.