Host: The Japanese Society of Toxicology
Name : The 47th Annual Meeting of the Japanese Society of Toxicology
Date : 2020 -
The implementation of the ICH S7B and E14 guidelines has been successful in preventing the introduction of potentially torsadogenic drugs to the market, but it has also unduly constrained drug development by focusing on only IKr block and QT prolongation as essential determinants of proarrhythmia risk.
Namely, the present surrogate markers such as IKr block or QT prolongation are highly sensitive but not very specific for predicting ventricular proarrhythmia risk; and there are clinically important drugs that block IKr but not proarrhythmic at therapeutic plasma concentrations. In response to these background, the comprehensive in vitro proarrhythmia assay (CiPA) initiative proposed the necessities of effects on multiple human cardiac current, in silico model based on electrophysiologic activity within a heart cell, and human stem-cell derived cardiomyocyte assays to confirm findings of in vitro and in silico assays.
We has started hERG and peak Nav1.5 current screening since 2017, Cav1.2 current screening since 2018, and late Nav1.5 current screening since 2019 using a SyncroPatch 384PE (Nanion Technologies GmbH). The SyncroPatch 384PE is a high throughput patch clamp instrument recording from up to 384 wells simultaneously. We will present the validation results of hERG, Cav1.2, peak Nav1.5, and late Nav1.5 current screening in this poster. When compared with the IC50 of these ion channel inhibitors and publication data, high correlative relationship was found. We would like to discuss how we should correspond to a novel strategy in conformity with a new paradigm.
