Mechanistic Model-Informed Proarrhythmic Risk Assessment of Drugs: Review of the "CiPA" Initiative and Design of a Prospective Clinical Validation Study

Clin Pharmacol Ther. 2018 Jan;103(1):54-66. doi: 10.1002/cpt.896. Epub 2017 Nov 16.


The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is developing and validating a mechanistic-based assessment of the proarrhythmic risk of drugs. CiPA proposes to assess a drug's effect on multiple ion channels and integrate the effects in a computer model of the human cardiomyocyte to predict proarrhythmic risk. Unanticipated or missed effects will be assessed with human stem cell-derived cardiomyocytes and electrocardiogram (ECG) analysis in early phase I clinical trials. This article provides an overview of CiPA and the rationale and design of the CiPA phase I ECG validation clinical trial, which involves assessing an additional ECG biomarker (J-Tpeak) for QT prolonging drugs. If successful, CiPA will 1) create a pathway for drugs with hERG block / QT prolongation to advance without intensive ECG monitoring in phase III trials if they have low proarrhythmic risk; and 2) enable updating drug labels to be more informative about proarrhythmic risk, not just QT prolongation.

Publication types

  • Review

MeSH terms

  • Arrhythmias, Cardiac* / chemically induced
  • Arrhythmias, Cardiac* / diagnosis
  • Arrhythmias, Cardiac* / prevention & control
  • Clinical Studies as Topic / methods
  • Clinical Studies as Topic / standards
  • Computer Simulation*
  • Drug Evaluation, Preclinical* / methods
  • Drug Evaluation, Preclinical* / standards
  • Electrocardiography / methods*
  • Humans
  • Risk Assessment / methods*
  • Validation Studies as Topic