Introduction to in silico model for proarrhythmic risk assessment under the CiPA initiative
10.12793/tcp.2019.27.1.12
- Author:
Jin Sol PARK
1
;
Ji Young JEON
;
Ji Ho YANG
;
Min Gul KIM
Author Information
1. Center for Clinical Pharmacology and Biomedical Research Institute, Chonbuk National University Hospital, Jeonju 54907, Republic of Korea. mgkim@jbnu.ac.kr
- Publication Type:Review
- Keywords:
Cardiotoxicity;
CiPA;
Torsade de Pointes
- MeSH:
Action Potentials;
Biomarkers;
Cardiotoxicity;
Computer Simulation;
Electrocardiography;
Hope;
Humans;
In Vitro Techniques;
Risk Assessment;
Sensitivity and Specificity;
Torsades de Pointes
- From:Translational and Clinical Pharmacology
2019;27(1):12-18
- CountryRepublic of Korea
- Language:English
-
Abstract:
In 2005, the International Council for Harmonization (ICH) established cardiotoxicity assessment guidelines to identify the risk of Torsade de Pointes (TdP). It is focused on the blockade of the human ether-à-go-go-related gene (hERG) channel known to cause QT/QTc prolongation and the QT/QTc prolongation shown on the electrocardiogram. However, these biomarkers are not the direct risks of TdP with low specificity as the action potential is influenced by multiple channels along with the hERG channel. Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative emerged to address limitations of the current model. The objective of CiPA is to develop a standardized in silico model of a human ventricular cell to quantitively evaluate the cardiac response for the cardiac toxicity risk and to come up with a metric for the TdP risk assessment. In silico working group under CiPA developed a standardized and reliable in silico model and a metric that can quantitatively evaluate cellular cardiac electrophysiologic activity. The implementation mainly consists of hERG fitting, Hill fitting, and action potential simulation. In this review, we explained how the in silico model of CiPA works, and briefly summarized current overall CiPA studies. We hope this review helps clinical pharmacologists to understand the underlying estimation process of CiPA in silico modeling.
