The views and opinions expressed in this paper are those of the authors, and do not necessarily reflect the official views of the Food and Drug Administration (FDA).
Tyrosine kinase inhibitor (TKI)-induced cardiotoxicity: approaches to narrow the gaps between preclinical safety evaluation and clinical outcome†
Article first published online: 10 SEP 2012
Published 2012. This article is a U.S. Government work and is in the public domain in the USA.
Journal of Applied Toxicology
Volume 32, Issue 12, pages 945–951, December 2012
How to Cite
Yang, B. and Papoian, T. (2012), Tyrosine kinase inhibitor (TKI)-induced cardiotoxicity: approaches to narrow the gaps between preclinical safety evaluation and clinical outcome. J. Appl. Toxicol., 32: 945–951. doi: 10.1002/jat.2813
- Issue published online: 24 OCT 2012
- Article first published online: 10 SEP 2012
- Manuscript Revised: 18 JUL 2012
- Manuscript Accepted: 18 JUL 2012
- Manuscript Received: 7 JUN 2012
- tyrosine kinase inhibitor;
- cardiac toxicity;
- isolated perfused heart;
- therapeutic index
Although therapies targeted to inhibit the activity of certain tyrosine kinases (TK) have helped advance cancer therapy in recent years, reports of cardiac toxicity following treatment with tyrosine kinase inhibitors (TKIs) were unexpected and not well predicted by preclinical studies. Such clinical findings exposed gaps in current preclinical drug testing for predicting the development of cardiac toxicities in humans. These gaps included a lack of a comprehensive TKI mechanism of action determination and appropriate cardiac functional evaluation. New preclinical approaches are suggested to address these issues. In addition to tyrosine kinase inhibition, other factors that may play a role in drug-induced cardiac effects should be assessed, such as unintended secondary targets of TKIs, toxic drug metabolites and drug accumulation in the heart. Both on-target and off-target toxic effects of TKIs on cultured cardiac myocytes have now been shown to be detectable, providing a rationale for using cardiomyocytes as a screening tool to study potential TKI-mediated cardiotoxicity. Incorporating isolated perfused heart methodology to chronic/subchronic rodent studies or including echocardiography in chronic large animal toxicity studies may improve the detection of changes in cardiac function over current methods, and they may eventually become a routine tool for screening drugs with suspected cardiotoxic potential. Further, assessing drug toxicity and efficacy together in an animal model of disease is highly informative for candidate drug selection, and should be encouraged to assess specific safety endpoints, such as cardiovascular function. Together, these approaches will help better close the gaps between preclinical testing and clinical outcomes. Published 2012. This article is a U.S. Government work and is in the public domain in the USA.