Molecularly targeted oncology therapeutics and prolongation of the QT interval.
Investigation and utilization of molecularly targeted agents has induced a number of drug adverse effects that are not typically associated with conventional chemotherapy. QT interval prolongation, a cardiac toxicity that increases the risk of fatal arrhythmia, is associated with several novel oncology therapies. Classes of molecularly targeted agents with described QT effects include histone deacetylase inhibitors, multitargeted tyrosine kinase inhibitors, vascular disruption agents, farnesyl protein transferase inhibitors, Src/Abl kinase inhibitors, and protein kinase C inhibitors. Concurrently, guidelines for monitoring the QT-prolonging effects of drugs under development have become increasingly rigorous. Although these guidelines apply to anticancer agents, they were not specifically designed for the oncology patient population. This article will review the pathophysiology of QT prolongation, methods of preclinical QT assessment, and current guidelines for QT evaluation in early phase trials. Additionally, molecularly targeted agents with QT effects will be summarized, and mechanisms of addressing this toxicity in the context of oncology drug development will be explored.
Strevel
Elizabeth L
EL
Division of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, Toronto, ON, Canada.
Ing
Douglas J
DJ
Siu
Lillian L
LL
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D017321:Clinical Trials, Phase I as Topic / Q000592:standards; D017322:Clinical Trials, Phase II as Topic / Q000592:standards; D017277:Drug Approval; D004353:Drug Evaluation, Preclinical; D004562:Electrocardiography; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D017410:Practice Guidelines as Topic; D011358:Product Surveillance, Postmarketing; D012307:Risk Factors; D014481:United States; D014486:United States Food and Drug Administration
D000970:Antineoplastic Agents