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.

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.
Cardiovasc Toxicol. 2019 Jul 06;:
Authors: Izumi-Nakaseko H, Fujiyoshi M, Hagiwara-Nagasawa M, Goto A, Chiba K, Kambayashi R, Naito AT, Ando K, Kanda Y, Ishii I, Sugiyama A
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 0.3 mg/kg was intravenously administered to the halothane-anesthetized dogs for 10 min with an interval of 20 min between the dosing (n = 4). Meanwhile, that at 0.1, 0.3, and 1 μM 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 ± 38 ng/mL (1.26 μM), respectively. The low dose decreased the heart rate, impaired the left ventricular mechanical function, and prolonged the ventricular effective refractory period. The high dose prolong...

Source: Cardiovascular Toxicology - July 5, 2019 Category: Cardiology Authors: Izumi-Nakaseko H, Fujiyoshi M, Hagiwara-Nagasawa M, Goto A, Chiba K, Kambayashi R, Naito AT, Ando K, Kanda Y, Ishii I, Sugiyama A Tags: Cardiovasc Toxicol Source Type: research