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Mechanisms, monitoring, and management of tyrosine kinase inhibitors-associated cardiovascular toxicities

Authors Chaar M, Kamta J, Ait-Oudhia S

Received 4 April 2018

Accepted for publication 19 July 2018

Published 25 September 2018 Volume 2018:11 Pages 6227—6237

DOI https://doi.org/10.2147/OTT.S170138

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 3

Editor who approved publication: Dr Faris Farassati


Maher Chaar,* Jeff Kamta,* Sihem Ait-Oudhia

Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USA

*These authors contributed equally to this work

Abstract: The tyrosine kinase inhibitor (TKI) drug class is a prominently used option in the treatment of various cancers. Safety evaluation of these drugs has shown evidence of cardiotoxicity of varying frequency and severity between agents; concern has led to updated labeling, warning prescribers of such. This review seeks to clarify the present dangers and investigate cardiotoxic mechanisms of action for each discussed TKI. Dasatinib was connected primarily with an incidence of fluid retention, edema, QT prolongation, and pulmonary hypertension in clinical studies. It is theorized that this is due to a combination of off-target kinase binding and on-target binding of Bcr-Abl, and less likely, mitochondrial induced apoptosis. Studies showed sorafenib to carry the risk of hypertension, QT prolongation, and myocardial infarction. Proposed mechanisms for these side effects include inhibition of proteins, vascular endothelium growth factor receptor, hERG potassium channels, and the RAF/MERK/ERK pro-survival pathway. Finally, lapatinib showed evidence of decreased left ventricular ejection fraction (LVEF) and QT prolongation in clinical studies. The literature attributes these as side effects of on-target ErbB2 binding leading to mitochondrial induced apoptosis. The concern warranted by these findings is in question. Pooled safety data suggest that the overall risk for cardiotoxicity is minimal in dasatinib and lapatinib. Sorafenib seems to carry a moderate concern. For the discussed agents, recommendations agree that routine monitoring via methods such as electroencephalogram, cardiac biomarkers, and blood pressure is warranted during the course of treatment, in addition to a comprehensive collection of past medical history and risk factors to identify those at heightened risk for cardiovascular events.

Keywords: cardiovascular toxicity, tyrosine kinase inhibitors, dasatinib, sorafenib, lapatinib

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