Incidence and relevance of QTc-interval prolongation caused by tyrosine kinase inhibitors

Kloth, Jacqueline S. L.; Pagani, A; Verboom, Michiel C.; Malovini, Alberto; Napolitano, Carlo; Kruit, Wim; Sleijfer, Stefan; Steeghs, Neeltje; Zambelli, Alberto; Mathijssen, Ron H.J.

doi:10.1038/bjc.2015.82

Cited by 92 publications

(64 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Erlotinib was predicted to have a high probability of inducing arrhythmia and myocardial infarction by the combined classifiers. In support of our model, recent studies reported that erlotinib induced QTc interval in patients 57 and CV damage in rat model. 58 In addition, an increasing number of clinical case reports of acute myocardial infarction following treatment by erlotinib in cancer patients also were reported.…”

Section: Resultssupporting

confidence: 88%

In SilicoPharmacoepidemiologic Evaluation of Drug-Induced Cardiovascular Complications Using Combined Classifiers

Cai

Fang

Guo

et al. 2018

J. Chem. Inf. Model.

View full text Add to dashboard Cite

Drug-induced cardiovascular complications are the most common adverse drug events and account for the withdrawal or severe restrictions on use of multitudinous post-marketed drugs. In this study, we developed new in silico models for systematic identification of drug-induced cardiovascular complications in drug discovery and post-marketing surveillance. Specifically, we collected drug-induced cardiovascular complications covering five most common types of cardiovascular outcomes (hypertension, heart block, arrhythmia, cardiac failure, and myocardial infarction) from four publicly available data resources: Comparative Toxicogenomics Database, SIDER, Offsides, and MetaADEDB. Using these databases, we developed a combined classifier framework through integration of five machine-learning algorithms: logistic regression, random forest, k-nearest neighbors, support vector machine, and neural network. The totality of models included 180 single classifiers with area under receiver operating characteristic curves (AUC) ranging from 0.647 to 0.809 on 5-fold cross validations. To develop the combined classifiers, we then utilized a neural network algorithm to integrate the best four single classifiers for each cardiovascular outcome. The combined classifiers had higher performance with an AUC range from 0.784 to 0.842 compared to single classifiers. Furthermore, we validated our predicted cardiovascular complications for 63 anticancer agents using experimental data from clinical studies, human pluripotent stem cell-derived cardiomyocyte assays, and literature. The success rate of our combined classifiers reached 87%. In conclusion, this study presents powerful in silico tools for systematic risk assessment of drug-induced cardiovascular complications. This tool is relevant not only in early stages of drug discovery, but throughout the life of a drug including clinical trials and post-marketing surveillance.

show abstract

Section: Resultssupporting

confidence: 88%

In SilicoPharmacoepidemiologic Evaluation of Drug-Induced Cardiovascular Complications Using Combined Classifiers

Cai

Fang

Guo

et al. 2018

J. Chem. Inf. Model.

View full text Add to dashboard Cite

show abstract

“…At baseline measurement, QTc intervals were significantly longer in females than in males (QTcfemales=404 ms vs QTcmales=399 ms, P=0.027) as expected. A statistically significant increase was observed in the individual treated with sunitinib, vemurafenib, sorafenib, imatinib, and erlotinib (median 0394;QTc ranging from +7 to +24 ms, P<0.004) 96 . Especially, patients treated with vemurafenib were at increased risk of developing a QTc of greater than or equal to 470 ms, a threshold associated with an increased risk for arrhythmias 96 .…”

Section: Multi-targeted Tyrosine Kinase Inhibitorsmentioning

confidence: 91%

“…Recently, a retrospective analysis was carried out on the multi-targeted tyrosine kinases. In this multicenter clinical trial four centers in the Netherlands and Italy screened patients who were treated with erlotinib, gefitinib, imatinib, lapatinib, pazopanib, sorafenib, sunitinib, or vemurafenib 96 . A total of 363 patients were eligible for the analyses.…”

Section: Multi-targeted Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Mechanisms of Cardiotoxicity of Cancer Chemotherapeutic Agents: Cardiomyopathy and Beyond

Moudgil

Yeh

2016

Canadian Journal of Cardiology

View full text Add to dashboard Cite

Tremendous strides have been made in the treatment of various oncological diseases such that patients are surviving longer and are having better quality of life. However, the success has been tainted by the iatrogenic cardiac toxicities. This is especially concerning in the younger population who are facing cardiac disease such as heart failure in their 30s and 40s as the consequence of the anthracycline’s side-effect (used for childhood leukemia and lymphoma). This resulted in the awareness of cardio-toxic effect of anticancer drugs and emergence of a new discipline: Onco-cardiology. Since then numerous anticancer drugs have been correlated to cardiomyopathy. Additionally, other cardiovascular effects have been identified which includes but no limited to the myocardial infarction, thrombosis, hypertension, arrhythmias and pulmonary hypertension. This review examines some of the anticancer agents mitigating cardiotoxicity and presents current knowledge of molecular mechanism(s). The aim of the review is to ignite awareness of emerging cardio-toxic effects as new generation of anticancer agents are being tested in clinical trials and introduced as part of therapeutic armamentarium to our oncological patients.

show abstract

“…Planning for dose escalation has been considered for their clinical use, as many malignancies are thought to be caused by an aberrant tyrosine kinase function [1][2][3]. However, some TKIs have been reported to cause a significant prolongation of the electrocardiographic QTc interval when used to treat patients with advanced carcinoma [4]. Various agents and conditions that cause 2 of 13 prolongation of the QTc interval may predispose an individual to tosade de pointes tachyarrhythmia, which may result in syncope or sudden death [5,6].…”

Section: Introductionmentioning

confidence: 99%

Differential Inhibitory Actions of Multitargeted Tyrosine Kinase Inhibitors on Different Ionic Current Types in Cardiomyocytes

Chang

Liu

Lee

et al. 2020

IJMS

View full text Add to dashboard Cite

Lapatinib (LAP) and sorafenib (SOR) are multitargeted tyrosine kinase inhibitors (TKIs) with antineoplastic properties. In clinical observations, LAP and SOR may contribute to QTc prolongation, but the detailed mechanism for this has been largely unexplored. In this study, we investigated whether LAP and SOR affect the activities of membrane ion channels. Using a small animal model and primary cardiomyocytes, we studied the impact of LAP and SOR on Na + and K + currents. We found that LAP-induced QTc prolongation in mice was reversed by isoproterenol. LAP or SOR suppressed the amplitude of the slowly activating delayed-rectifier K + current (I K(S) ) in H9c2 cells in a time-and concentration-dependent fashion. The LAP-mediated inhibition of I K(S) was reversed by adding isoproterenol or meclofenamic acid, but not by adding diazoxide. The steady-state activation curve of I K(S) during exposure to LAP or SOR was shifted toward a less negative potential, with no change in the gating charge required to activate the current. LAP shortened the recovery from I K(S) deactivation. As rapid repetitive stimuli, the I K(S) amplitude decreased; however; the LAP-induced inhibition of I K(S) remained effective. LAP or SOR alone also suppressed inwardly rectifying K + and voltage-gated Na + current in neonatal rat ventricular myocytes. The inhibition of ionic currents during exposure to TKIs could be an important mechanism underlying changes in QTc intervals.

show abstract

Incidence and relevance of QTc-interval prolongation caused by tyrosine kinase inhibitors

Cited by 92 publications

References 22 publications

In SilicoPharmacoepidemiologic Evaluation of Drug-Induced Cardiovascular Complications Using Combined Classifiers

In SilicoPharmacoepidemiologic Evaluation of Drug-Induced Cardiovascular Complications Using Combined Classifiers

Mechanisms of Cardiotoxicity of Cancer Chemotherapeutic Agents: Cardiomyopathy and Beyond

Differential Inhibitory Actions of Multitargeted Tyrosine Kinase Inhibitors on Different Ionic Current Types in Cardiomyocytes

Contact Info

Product

Resources

About