Brown, Alan, Friedrichs, Gregory, Traebert, Martin, Weber, Valerie, Yao, Nancy, Tang, Hai-Ming and Yan, Gan-Xin (2024) Electrophysiological changes in the rabbit ventricular wedge assay and in human-induced pluripotent stem-cell derived (IPSC) cardiomyocytes provided correlates to severe arrhythmia observed in a dog toxicology study, whereas standard in vitro ion channel assays were not predictive of adverse cardiovascular change. International Journal of Toxicology. pp. 1-12. ISSN DOI: 10.1177/10915818241230900

Abstract

During the drug discovery process, low molecular weight compounds are typically assayed in vitro for secondary pharmacology or “off-target” effects, which includes ion channels relevant to cardiac physiology. These assays generally preceed testing in animals. Compound A was an irreversible inhibitor of myeloperoxidase investigated for treatment of peripheral artery disease. Oral doses in dogs at ≥5 mg/kg resulted in cardiac arrhythmias in a dose-dependent fashion (at Cmax,free ≥1.53 µM) that progressed in severity with time. Nevertheless, a panel of 13 ion channel (K, Na, Ca) assays, including hERG, did not identify pharmacologic risks of the molecule. Compound A and related Compound B were subsequently evaluated for electrophysiological effects in the isolated rabbit ventricular wedge assay. Compounds A and B prolonged QT and Tp-e intervals at ≥1 and ≥0.3 µM, respectively, and both prolonged QRS at ≥5 µM. Compound A produced early after depolarizations and premature ventricular complexes at ≥5 µM. These data indicate both compounds can inhibit hERG (Ikr) and Nav1.5 ion channels. In human IPSC cardiomyocytes, Compounds A and B prolonged field potential duration at ≥3 µM and induced cellular dysrhythmia at ≥10 and ≥3 µM, respectively, further supporting a pro-arrhythmic liability. In a repeat-dose rat toxicology study, heart tissue:plasma concentration ratios for Compound A were ≥19X at 24 hours post-dose, indicating significant distribution into cardiac tissue. In conclusion, in vitro ion channel assays may not identify cardiovascular risks observed in vivo, which can be affected by tissue drug distribution. Risk for arrhythmia may increase with a “trappable” ion channel inhibitor, particularly if cardiac tissue drug levels achieve a critical threshold for pharmacologic effect.

Item Type:	Article
Keywords:	cardiovascular safety, arrhythmia, ion channels, hERG assay
Date Deposited:	21 May 2024 00:46
Last Modified:	21 May 2024 00:46
URI:	https://oak.novartis.com/id/eprint/51438