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.
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 and reversible posterior leukoencephalopathy syndrome. Vandetanib is available only through a restricted distribution program that requires certification and regular monitoring.
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.
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
Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) or any elevations accompanied by jaundice or symptoms should lead to dose reduction or temporary cessation. There does not appear to be cross reactivity in risk for hepatic injury between vandetanib and other tyrosine kinase inhibitors.
REPRESENTATIVE TRADE NAMES
Vandetanib – Generic, Caprelsa®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 25 July 2014
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Wells SA Jr, Gosnell JE, Gagel RF, Moley J, Pfister D, Sosa JA, Skinner M, et al. Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Oncol 2010; 28: 767-72. PubMed Citation (Among 30 patients with advanced or metastatic hereditary medullary thyroid cancer [with activating RET mutations] treated with vandetanib for an average of 18.8 months, partial responses occurred in 20% of patients and common side effects were hypertension [77%], diarrhea [70%], rash [67%], fatigue [63%] and nausea [63%]; no mention of ALT elevations or hepatotoxicity).
Leboulleux S, Bastholt L, Krause T, de la Fouchardiere C, Tennvall J, Awada A, Gómez JM, et al. Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial. Lancet Oncol 2012; 13: 897-905. PubMed Citation (Among 145 patients with advanced or metastatic differentiated thyroid cancer, median progression free survival was 11.1 months in those receiving vandetanib vs 5.9 months with placebo; no mention of ALT elevations or hepatotoxicity, but QTc prolongation occurred in 23%).
Deshpande HA, Sheth K, Sosa JA, Roman S. Efficacy and tolerability of pharmacotherapy options for the treatment of medullary thyroid cancer. Clin Med Insights Oncol 2012; 6: 355-62. PubMed Citation (Review of the rationale for use, mechanism of action, pharmacology, efficacy, safety and cost of vandetanib for medullary thyroid cancer, mentions that ALT elevations were reported in 3-5% of treated patients).
Wells SA Jr, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, Baudin E, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol 2012; 30: 134-41. PubMed Citation (Among 331 patients with advanced or metastatic medullary thyroid cancer, median progression free survival was 30.5 months with vandetanib vs 19.3 months with placebo; extensive discussion of adverse events does not mention ALT elevations or hepatotoxicity).
Vandetanib (Caprelsa) for medullary thyroid cancer. Med Lett Drugs Ther 2012; 54 (1381): 3-4. PubMed Citation (Concise review of the mechanism of action, efficacy, safety and costs of vandetanib for medullary thyroid cancer shortly after its approval in the US, mentions severe adverse events of QTc prolongation, sudden death, skin reactions, photosensitivity and Stevens Johnson syndrome, but not hepatotoxicity or ALT elevations).
Spraggs CF, Xu CF, Hunt CM. Genetic characterization to improve interpretation and clinical management of hepatotoxicity caused by tyrosine kinase inhibitors. Pharmacogenomics 2013; 14: 541-54. PubMed Citation (Review of genetic associations of serum ALT and bilirubin elevations during therapy with tyrosine kinase inhibitors, focusing on lapatinib and pazopanib).
Shah RR, Morganroth J, Shah DR. Hepatotoxicity of tyrosine kinase inhibitors: clinical and regulatory perspectives. Drug Saf 2013; 36: 491-503. PubMed Citation (Review of the hepatotoxicity of 18 tyrosine kinase inhibitors approved for use in cancer in the US as of 2013; vandetanib is associated with some degree of ALT elevation in 51% of patients and in elevations above 5 times ULN in 2%, but has not been linked to cases of clinically apparent hepatitis or hepatic failure).
Ton GN, Banaszynski ME, Kolesar JM. Vandetanib: a novel targeted therapy for the treatment of metastatic or locally advanced medullary thyroid cancer. Am J Health Syst Pharm 2013; 70: 849-55. PubMed Citation (Review of the efficacy and safety of vandetanib as therapy of medullary thyroid cancer does not mention ALT elevations or hepatotoxicity).
Lacouture ME, Ciccolini K, Kloos RT, Agulnik M. Overview and management of dermatologic events associated with therapies for medullary thyroid cancer. Thyroid 2014; 62: 798-806. PubMed Citation (Description of the spectrum of skin toxicities of kinase inhibitors including vandetanib used in treatment of medullary thyroid cancer mentions that inhibition of EGFR signaling causes growth arrest and apoptosis in keratinocytes, with subsequent release of cytokines and recruitment of inflammatory cells).
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