title: Proarrhythmia liability assessment and the comprehensive in vitro Proarrhythmia Assay (CiPA): An industry survey on current practice.
abstract: BACKGROUND
  The Safety Pharmacology Society (SPS) has conducted a survey of its membership to identify industry practices related to testing considered in the Comprehensive In vitro Proarrhythmia Assay (CiPA).
  
  
  METHODS
  Survey topics included nonclinical approaches to address proarrhythmia issues, conduct of in silico studies, in vitro ion channel testing methods used, drugs used as positive controls during the conduct of cardiac ion channel studies, types of arrhythmias observed in non-clinical studies and use of the anticipated CiPA ion channel assay.
  
  
  RESULTS
  In silico studies were used to evaluate effects on ventricular action potentials by only 15% of responders. In vitro assays were used mostly to assess QT prolongation (95%), cardiac Ca2+and Na+channel blockade (82%) and QT shortening or QRS prolongation (53%). For de-risking of candidate drugs for proarrhythmia, those assays most relevant to CiPA including cell lines stably expressing ion channels used to determine potency of drug block were most frequently used (89%) and human stem cell-derived or induced pluripotent stem cell cardiomyocytes (46%). Those in vivo assays related to general proarrhythmia derisking include ECG recording using implanted telemetry technology (88%), jacketed external telemetry (62%) and anesthetized animal models (53%). While the CiPA initiative was supported by 92% of responders, there may be some disconnect between current practice and future expectations, as explained.
  
  
  CONCLUSIONS
  Proarrhythmia liability assessment in drug development presently includes study types consistent with CiPA. It is anticipated that CiPA will develop into a workable solution to the concern that proarrhythmia liability testing remains suboptimal.
authors.affiliation: CiToxLAB North America, 445, Armand-Frappier Boul, Laval, QC H7V 4B3, Canada. Electronic address: authiers@ca.citoxlab.com.
authors.forename: Simon
authors.initials: S
authors.lastname: Authier
authors.affiliation: Department of Toxicology & PKDM, Purdue Pharma L.P., Cranbury, NJ 08512, USA.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Pugsley
authors.affiliation: Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 20993, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Koerner
authors.affiliation: Safety & Toxicology Assessment, Coyne Scientific, Atlanta, GA 30303, USA.
authors.forename: Bernard
authors.initials: B
authors.lastname: Fermini
authors.affiliation: Drug Safety & Metabolism, AstraZeneca, Cambridge CB4 0WG, UK.
authors.forename: William S
authors.initials: WS
authors.lastname: Redfern
authors.affiliation: Non-Clinical Development, UCB-Biopharma, Belgium.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Valentin
authors.affiliation: Integrated Discovery and Safety Pharmacology, Amgen, Inc., Thousand Oaks, CA, USA.
authors.forename: Hugo M
authors.initials: HM
authors.lastname: Vargas
authors.affiliation: Lilly Corporate Center, Eli Lilly & Co, Indianapolis, IN, USA.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Leishman
authors.affiliation: Safety Pharmacology Society, Washington, DC, USA.
authors.forename: Krystle
authors.initials: K
authors.lastname: Correll
authors.affiliation: Cardiovascular Division, Faculty of Life Sciences & Medicine, King's College London, Rayne Institute, St Thomas' Hospital, London SE17EH, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Curtis
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003198:Computer Simulation; D004345:Drug Industry; D004562:Electrocardiography / Q000187:drug effects; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D007473:Ion Channels; D008133:Long QT Syndrome / Q000139:chemically induced; D032383:Myocytes, Cardiac / Q000187:drug effects; D026941:Sodium Channel Blockers / Q000494:pharmacology; D011795:Surveys and Questionnaires; D013686:Telemetry
chemical_list: D002121:Calcium Channel Blockers; D007473:Ion Channels; D026941:Sodium Channel Blockers