Referenced in: none

Automatically associated channels: Kv11.1

Title: CSAHi study: Validation of multi-electrode array systems (MEA60/2100) for prediction of drug-induced proarrhythmia using human iPS cell-derived cardiomyocytes -Assessment of inter-facility and cells lot-to-lot-variability.

Authors: Yumiko Nozaki, Yayoi Honda, Hitoshi Watanabe, Shota Saiki, Kiyotaka Koyabu, Tetsuji Itoh, Chiho Nagasawa, Chiaki Nakamori, Chiaki Nakayama, Hiroshi Iwasaki, Shinobu Suzuki, Ikumi Washio, Etsushi Takahashi, Kaori Miyamoto, Atsuhiro Yamanishi, Hiroko Endo, Junko Shinozaki, Hisashi Nogawa, Takeshi Kunimatsu

Journal, date & volume: Regul. Toxicol. Pharmacol., 2016 Feb 13 , ,

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/26884090

Abstract
In vitro screening of hERG channels are recommended under ICH S7B guidelines to predict drug-induced QT prolongation and Torsade de Pointes (TdP), whereas proarrhythmia is known to be evoked by blockage of other ion channels involved in cardiac contraction and compensation mechanisms. A consortium for drug safety assessment using human iPS cells-derived cardiomyocytes (hiPS-CMs), CSAHi, has been organized to establish a novel in vitro test system that would enable better prediction of drug-induced proarrhythmia and QT prolongation. Here we report the inter-facility and cells lot-to-lot variability evaluated with FPDc (corrected field potential duration), FPDc10 (10% FPDc change concentration), beat rate and incidence of arrhythmia-like waveform or arrest on hiPS-CMs in a multi-electrode array system. Arrhythmia-like waveforms were evident for all test compounds, other than chromanol 293B, that evoked FPDc prolongation in this system and are reported to induce TdP in clinical practice. There was no apparent cells lot-to-lot variability, while inter-facility variabilities were limited within ranges from 3.9- to 20-folds for FPDc10 and about 10-folds for the minimum concentration inducing arrhythmia-like waveform or arrests. In conclusion, the new assay model reported here would enable accurate prediction of a drug potential for proarrhythmia.