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Comprehensive in Vitro Pro‐arrhythmic Assays Demonstrate That Omecamtiv Mecarbil Has Low Pro‐arrhythmic Risk by Yusheng Qu; BaoXi Gao; Ziva Arimura; Mei Fang; Hugo M. Vargas is a Medicine article available to read on EtoBox.

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## Abstract Omecamtiv mecarbil (OM) is a myosin activator (myotrope), developed as a potential therapeutic agent for heart failure with reduced ejection fraction. To characterize the potential pro‐arrhythmic risk of this novel sarcomere activator, we evaluated OM in a series of International Conference on Harmonization S7B core and follow‐up assays, including an in silico action potential (AP) model. OM was tested in: (i) hERG, Nav1.5 peak, and Cav1.2 channel assays; (ii) in silico computation in a human ventricular AP (hVAP) population model; (iii) AP recordings in canine cardiac Purkinje fibers (PF); and (iv) electrocardiography analysis in isolated rabbit hearts (IRHs). OM had low potency in the hERG (half‐maximal inhibitory concentration [IC~50~] = 125.5 μM) and Nav1.5 and Cav1.2 assays (IC~50~ > 300 μM). These potency values were used as inputs to investigate the occurrence of repolarization abnormalities (biomarkers of pro‐arrhythmia) in an hVAP model over a wide range of OM concentrations. The outcome of hVAP analysis indicated low pro‐arrhythmia risk at OM concentration up to 30 μM (100‐fold the effective free therapeutic plasma concentration). In the isolated canine PF ass

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Author

Yusheng Qu; BaoXi Gao; Ziva Arimura; Mei Fang; Hugo M. Vargas

Publisher

Wiley

Published

2021

Language

EN

Field

Medicine (Health Sciences)