Dasatinib can Impair Left Ventricular Mechanical Function But May Lack Proarrhythmic Effect: A Proposal of Non-clinical Guidance for Predicting Clinical Cardiovascular Adverse Events of Tyrosine Kinase Inhibitors

Abstract

Tyrosine kinase inhibitors are known to clinically induce various types of cardiovascular adverse events; however, it is still difficult to predict them at preclinical stage. In order to explore how to better predict such drug-induced cardiovascular adverse events, we tried to develop a new protocol by assessing acute electrophysiological, cardiohemodynamic, and cytotoxic effects of dasatinib in vivo and in vitro. Dasatinib at 0.03 and 0.3mg/kg was intravenously administered to the halothane-anesthetized dogs for 10min with an interval of 20min between the dosing (n = 4). Meanwhile, that at 0.1, 0.3, and 1μM was cumulatively applied to the human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) (n = 7). In the dogs, the low and high doses provided peak plasma concentrations of 40 ± 5 (0.08) and 615 ± 38ng/mL (1.26μM), respectively. The low dose decreased the heart rate, impaired the left ventricular mechanical function, and prolonged the ventricular effective refractory period. The high dose prolonged the repolarization period, induced hemorrhagic tendency, and increased plasma cardiac troponin I level in addition to enhancement of the changes observed after the low dose, whereas it neither affected the cardiac conduction nor induced ventricular arrhythmias. In the hiPSC-CMs, dasatinib prolonged the repolarization and refractory periods like in dogs, while it did not induce apoptotic or necrotic process, but that it increased the conduction speed. Clinically observed major cardiovascular adverse events of dasatinib were observed qualitatively by currently proposed assay protocol, which may become a useful guide for predicting the cardiotoxicity of new tyrosine kinase inhibitors.