The V804M mutation inRET confers resistance to Vandetanib anti-RET activity.[9]
In people with moderate and severe hepatic impairment, no dosage for vandetanib has been recommended, as its safety and efficacy has not been established yet.[10] Vandetanib is contraindicated in people with congenitallong QT syndrome.[2][5]
Vandetanib has been reported as a substrate for theOATP1B1 andOATP1B3 transporters. Interaction of vandetanib with OATP1B1 and OATP1B3 may alter its hepatic disposition and can lead to transporter mediated drug-drug interactions.[10] Also, vandetanib is an inhibitor of OATP1B3 transporter but not for OATP1B1.[12]
Other drugs thatprolong the QT interval can possibly add to this side effect of vandetanib. As the drug is partly metabolised via the liver enzymeCYP3A4, stronginducers of this enzyme can decrease its blood plasma concentrations. CYP3A4 inhibitors do not significantly increase vandetanib concentrations, presumably because it is also metabolised byflavin containing monooxygenase 1 (FMO1) and3.[2][5]
Metabolites of vandetanib (top left):N-desmethylvandetanib (bottom left, viaCYP3A4), vandetanib-N-oxide (bottom right, viaFMO1 andFMO3), both pharmacologically active, and a minor amount of aglucuronide.[14]
Vandetanib is well absorbed from the gut, reaches peak blood plasma concentrations 4 to 10 hours after application, and has a half-life of 19 days on average, per pharmacokinetic studies. It has to be taken for about three months to achieve a steady-state concentration. In the blood, it is almost completely (90–96%) bound to plasma proteins such asalbumin. It is metabolised toN-desmethylvandetanib via CYP3A4 and to vandetanib-N-oxide via FMO1 and 3. Both of these areactive metabolites. Vandetanib is excreted via the faeces (44%) and the urine (25%) in form of the unchanged drug and the metabolites.[5][15][14]
AstraZeneca tested Vandetanib in clinical trials fornon-small cell lung cancer and submitted an application for approval to the EMA but then withdrew the application in October 2009 after trials showed no benefit when the drug was administered alongside chemotherapy.[19] A clinical trial of vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastaticpancreatic carcinoma was negative in a prospective, randomised, double-blind, multicentre phase 2 trial.[20]
^abcd"UK label".www.medicines.org.uk. UK Electronic Medicines Compendium. 16 December 2016. Archived fromthe original on 28 February 2017. Retrieved27 February 2017.
^Martin P, Oliver S, Kennedy SJ, Partridge E, Hutchison M, Clarke D, et al. (January 2012). "Pharmacokinetics of vandetanib: three phase I studies in healthy subjects".Clinical Therapeutics.34 (1):221–237.doi:10.1016/j.clinthera.2011.11.011.PMID22206795.
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