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
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 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.
KeywordsDasatinib Halothane-anesthetized dogs Human induced pluripotent stem cell-derived cardiomyocytes Safety pharmacology
The authors thank Dr. Yuji Nakamura for the conduct of in vivo experiments and the data analysis, Mrs. Yuri Ichikawa for technical assistance, Mr. Kentaro Tanaka and Miss Hikaru Tsuruoka for in vitro data analysis, and Alpha MED Scientific, Inc. for technical advice.
This work was supported by JSPS KAKENHI Grant Number 17K08608 (to HI-N), 15K08246 (to KA), and 16K08559 (to AS); AMED Grant 18mk0104117j0001 (to YK); AMED Grant 18am0101122j0002 (to ATN and AS); Toho University’s 60th anniversary (to KA); and Initiative for Realizing Diversity in the Research Environment (to HI-N).
Compliance with Ethical Standards
Conflict of interest
The authors indicated no potential conflicts of interest for this study project.
All experiments were approved by the Animal Research Committee for Animal Experimentation of Toho University (No. 17-52-324) and performed in accordance with the Guidelines for the Care and Use of Laboratory Animals of Toho University and Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines for reporting experiments involving animals [44, 45].
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