title: Tyrosine kinase inhibitor (TKI)-induced cardiotoxicity: approaches to narrow the gaps between preclinical safety evaluation and clinical outcome.
abstract: 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.
authors.affiliation: Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA. baichun.yang@fda.hhs.gov
authors.forename: Baichun
authors.initials: B
authors.lastname: Yang
authors.forename: Thomas
authors.initials: T
authors.lastname: Papoian
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic / Q000379:methods* / Q000592:standards; D003226:Congresses as Topic; D004353:Drug Evaluation, Preclinical / Q000379:methods* / Q000592:standards; D015507:Drugs, Investigational / Q000009:adverse effects* / Q000627:therapeutic use; D006331:Heart Diseases / Q000139:chemically induced* / Q000201:enzymology; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D015507:Drugs, Investigational; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases