Brown, Alan, Friedrichs, Gregory, Tang, Hai-Ming, Weber, Valerie, Traebert, Martin, Yao, Nancy and Yan, Gan-Xin Electrophysiological changes observed in the rabbit ventricular wedge assay and in human-induced pluripotent stem-cell derived (iPS) cardiomyocytes correlated with severe arrhythmia observed in vivo, whereas standard in vitro ion channel assays were not predictive of effects seen.

Abstract

UTT780 is a low molecular weight irreversible inhibitor of myeloperoxidase investigated as a potential therapy for peripheral artery disease. A single oral dose of UTT780 in dogs at ≥5 mg/kg resulted in severe and prolonged arrhythmias as determined using jacketed ECG telemetry equipment. Premature ventricular contractions, bigeminy, ventricular tachycardia and atrial-ventricular block were observed in a dose-dependent fashion (at Cmax,free ≥1.67 µM) that progressed in severity over time. Nevertheless, a panel of 13 ion channel (K, Na, Ca) assays, including HERG, did not identify pharmacologic risks of the molecule. UTT780 and a related compound, MEP646, were subsequently evaluated for electrophysiological effects in the isolated rabbit ventricular wedge assay. UTT780 and MEP646 prolonged QT and Tp-e intervals at ≥1 and ≥0.3 µM, respectively, and both compounds prolonged QRS at ≥5 µM. UTT780 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 iPS cardiomyocytes, both UTT780 and MEP646 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 UTT780 concentration ratios were ≥19X at 24 hours post-dose. 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 effect.

Item Type:	Article
Date Deposited:	01 Sep 2023 00:46
Last Modified:	01 Sep 2023 00:46
URI:	https://oak.novartis.com/id/eprint/48393