FDA evaluation of hepatotoxicity related to tyrosine kinase inhibitors.

3106 Background: Tyrosine kinase inhibitors (TKIs) interfere with several critical signal transduction pathways in cancer. Nine TKIs have been FDA approved to treat a variety of malignancies. TKIs have been associated with severe liver injury (SLI). Whether this liver injury is a class effect, or specific to certain TKIs is being investigated. Methods: Analyses included evaluation of postmarketing reports of SLI associated with 9 TKIs (imatinib, dasatinib, nilotinib, erlotinib, gefitinib, lapatinib, sorafenib, sunitinib, and pazopanib) from FDA’s Adverse Event Reporting System (AERS) and literature review. SLI is defined as acute liver injury (elevated LFTs, bilirubinemia, or jaundice) in combination with one of the following events: death, liver transplantation or placement on liver transplant list, hepatic encephalopathy, coagulopathy or renal impairment. Clinical toxicity data, demographics, drug metabolism, laboratory, pharmacokinetic and exposure data were reviewed from new drug application (NDA) sub...