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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Vandetanib

Last Update: June 28, 2018.

OVERVIEW

Introduction

Vandetanib is a multi-kinase inhibitor that is used in the therapy of advanced or metastatic medullary thyroid cancer. Vandetanib therapy is commonly associated with transient elevations in serum aminotransferase during therapy, but has not been linked to cases of clinically apparent acute liver injury with jaundice.

Background

Vandetanib (van det’ a nib) is an orally available, multi-kinase inhibitor with activity against vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) receptor families as well as RET (rearranged-during-transfection), BRK, TIE2 and Src kinases. Vandetanib has potent anti-angiogenesis activity and specific potency against mutant RET tyrosine kinases that are found in most hereditary and a large proportion of spontaneous medullary thyroid cancers. Clinical trials of vandetanib in advanced or metastatic medullary thyroid cancer have documented significant prolongation of progression free survival. Vandetanib received approval for use in the United States in 2011 and current indications are for symptomatic or progressive, unresectable or metastatic medullary thyroid cancer. Vandetanib is available in tablets of 100 and 300 mg under the brand name Caprelsa, and the recommended initial dose is 300 mg once daily. Side effects are common and can be problematic and even fatal. The most frequent adverse events include diarrhea, nausea, fatigue, rash, acne, hypertension, headache, anorexia and abdominal pain. Less common, but potentially severe side effects include prolongation of the QTc interval, heart failure, sudden death, severe skin toxicity, Stevens Johnson syndrome, interstitial lung disease, hemorrhage, ischemic cerebrovascular events, reversible posterior leukoencephalopathy syndrome and embryo-fetal toxicity. Vandetanib is available only through a restricted distribution program that requires certification and regular monitoring.

Hepatotoxicity

In large clinical trials of vandetanib, abnormalities in routine liver tests were common with serum aminotransferase elevations, occurring in up to half of patients and rising above 5 times the upper limit of normal (ULN) 2% to 5% of patients. In prelicensure trials of vandetanib in thyroid cancer, there were no reports of clinically apparent liver injury with jaundice or hepatic failure. Since approval and more wide scale use, there have been no published reports of hepatotoxicity due to vandetanib and the product label does not include discussion of hepatotoxicity. However, many of the kinase inhibitors used in cancer chemotherapy have been implicated in cases of clinically apparent liver injury which typically arises within the first 2 to 12 weeks of therapy, presenting with symptoms of fatigue, nausea and jaundice and a hepatocellular pattern of serum enzyme elevations without immunoallergic or autoimmune features. Several tyrosine kinase inhibitors (imatinib, nilotinib) have also been implicated in causing reactivation of hepatitis B.

Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism of injury accounting for serum enzyme elevations during vandetanib therapy is not known. Vandetanib has a long plasma half life (~19 days). Small amounts are metabolized in the liver through the CYP 3A4 pathway and it is susceptible to drug-drug interactions with strong inducers or inhibitors of hepatic CYP 3A4 activity.

Outcome and Management

In using kinase inhibitors to the therapy of cancer, routine monitoring of liver tests before and during therapy is warranted. Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) or any elevations accompanied by jaundice or symptoms should lead to temporary cessation. Vantetanib should be restarted only if serum enzyme abnormalities resolve or improve and only with careful monitoring. There does not appear to be cross reactivity in risk for hepatic injury between vandetanib and other tyrosine kinase inhibitors.

Drug Class: Antineoplastic Agents, Protein Kinase Inhibitors

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Vandetanib – Generic, Caprelsa®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NO.MOLECULAR FORMULASTRUCTURE
Vandetanib 443913-73-3 C22-H24-Br-F-N4-O2
Vandetanib chemical structure

ANNOTATED BIBLIOGRAPHY

References updated: 28 June 2018

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