Vandetanib#Clinical trials

Vandetanib is used to treat medullary thyroid cancer in adults who are ineligible for surgery.{{cite web | title=Caprelsa- vandetanib tablet, film coated | website=DailyMed | date=19 June 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e5721cb8-4185-47b9-bbb3-1c587e558a03 | access-date=8 December 2020}}{{cite web|title=UK label|url=https://www.medicines.org.uk/emc/medicine/26040|website=www.medicines.org.uk|publisher=UK Electronic Medicines Compendium|access-date=27 February 2017|language=en|date=16 December 2016|archive-date=28 February 2017|archive-url=https://web.archive.org/web/20170228083513/https://www.medicines.org.uk/emc/medicine/26040|url-status=dead}}{{cite journal | vauthors = Viola D, Valerio L, Molinaro E, Agate L, Bottici V, Biagini A, Lorusso L, Cappagli V, Pieruzzi L, Giani C, Sabini E, Passannati P, Puleo L, Matrone A, Pontillo-Contillo B, Battaglia V, Mazzeo S, Vitti P, Elisei R | title = Treatment of advanced thyroid cancer with targeted therapies: ten years of experience | journal = Endocrine-Related Cancer | volume = 23 | issue = 4 | pages = R185–R205 | date = April 2016 | pmid = 27207700 | doi = 10.1530/ERC-15-0555 | doi-access = free }}

The V804M mutation in RET confers resistance to Vandetanib anti-RET activity.

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.{{cite journal | vauthors = Khurana V, Minocha M, Pal D, Mitra AK | title = Role of OATP-1B1 and/or OATP-1B3 in hepatic disposition of tyrosine kinase inhibitors | journal = Drug Metabolism and Drug Interactions | volume = 29 | issue = 3 | pages = 179–190 | date = March 2014 | pmid = 24643910 | pmc = 4407685 | doi = 10.1515/dmdi-2013-0062 }} Vandetanib is contraindicated in people with congenital long QT syndrome.{{cite web|publisher=Drugs.com|url=https://www.drugs.com/monograph/vandetanib.html|title=Vandetanib Monograph|access-date=29 August 2012}}

Very common (present in greater than 10% of people) adverse effects include colds, bronchitis, upper respiratory tract infections, urinary tract infections, decreased appetite, low calcium absorption, insomnia, depressed mood, Headache, tingling sensations, weird, painful sensations, dizziness, blurred vision, damage to the cornea, long QT syndrome, high blood pressure, stomach pain, diarrhea, nausea, vomiting, indigestion, sensitivity to sunlight, rash, acne, dry and itchy skin, nail disorders, protein in urine, kidney stones, weakness, fatigue, pain, and edema.

Common (present in between 1% and 10% of people) adverse effects include pneumonia, sepsis, influenza, cystitis, sinusitis, laryngitis, folliculitis, boils, fungal infection, kidney infections, low thyroid hormone levels, low potassium, high calcium levels, hyperglycemia, hypercholesterolemia, hypertriglyceridemia,{{cite journal | vauthors = Acitelli E, Maiorca C, Grani G, Maranghi M | title = Metabolic adverse events of multitarget kinase inhibitors: a systematic review | journal = Endocrine | volume = 81 | issue = 1 | pages = 16–29 | date = July 2023 | pmid = 37067769 | pmc = 10239378 | doi = 10.1007/s12020-023-03362-2 }} dehydration, low sodium levels, anxiety, tremor, lethargy, loss of consciousness, balance disorders, changes in sense of taste, visual impairment, halo vision, perceived light flashes, glaucoma, pink eye, dry eye, keratopathy, hypertensive crisis, mini strokes, nose bleeds, coughing up blood, defecating blood, colitis, dry mouth, stomatitis, constipation, gastritis, gallstones, Chemotherapy-induced acral erythema, hair loss, painful urination, bloody urine, kidney failure, frequent urination, urgent need to urinate, and fever.

Vandetanib has been reported as a substrate for the OATP1B1 and OATP1B3 transporters. Interaction of vandetanib with OATP1B1 and OATP1B3 may alter its hepatic disposition and can lead to transporter mediated drug-drug interactions. Also, vandetanib is an inhibitor of OATP1B3 transporter but not for OATP1B1.{{cite journal | vauthors = Khurana V, Minocha M, Pal D, Mitra AK | title = Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors | journal = Drug Metabolism and Drug Interactions | volume = 29 | issue = 4 | pages = 249–259 | date = May 2014 | pmid = 24807167 | pmc = 4407688 | doi = 10.1515/dmdi-2014-0014 }}

Other drugs that prolong the QT interval can possibly add to this side effect of vandetanib. As the drug is partly metabolised via the liver enzyme CYP3A4, strong inducers of this enzyme can decrease its blood plasma concentrations. CYP3A4 inhibitors do not significantly increase vandetanib concentrations, presumably because it is also metabolised by flavin containing monooxygenase 1 (FMO1) and 3.

Vandetanib is an inhibitor of vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and RET tyrosine kinases. RET tyrosine kinases; it weakly inhibits vascular endothelial growth factor receptor-3.{{cite journal | vauthors = Carlomagno F, Vitagliano D, Guida T, Ciardiello F, Tortora G, Vecchio G, Ryan AJ, Fontanini G, Fusco A, Santoro M | title = ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases | journal = Cancer Research | volume = 62 | issue = 24 | pages = 7284–7290 | date = December 2002 | pmid = 12499271 | url = http://cancerres.aacrjournals.org/content/62/24/7284.long }}

File:Vandetanib metabolism.svg), vandetanib-N-oxide (bottom right, via FMO1 and FMO3), both pharmacologically active, and a minor amount of a glucuronide.]]

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 as albumin. It is metabolised to N-desmethylvandetanib via CYP3A4 and to vandetanib-N-oxide via FMO1 and 3. Both of these are active metabolites. Vandetanib is excreted via the faeces (44%) and the urine (25%) in form of the unchanged drug and the metabolites.{{cite journal | vauthors = Martin P, Oliver S, Kennedy SJ, Partridge E, Hutchison M, Clarke D, Giles P | title = Pharmacokinetics of vandetanib: three phase I studies in healthy subjects | journal = Clinical Therapeutics | volume = 34 | issue = 1 | pages = 221–237 | date = January 2012 | pmid = 22206795 | doi = 10.1016/j.clinthera.2011.11.011 }}{{cite web|url=http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022405Orig1s000ClinPharmR.pdf|archive-url=https://web.archive.org/web/20140714163544/http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022405Orig1s000ClinPharmR.pdf|url-status=dead|archive-date=July 14, 2014|title=Clinical Pharmacology Review: Vandetanib|publisher=US Food and Drug Administration, Center for Drug Evaluation and Research|date=20 August 2010|access-date=29 August 2012}}

Vandetanib was approved by the FDA in April 2011, for treatment of late-stage thyroid cancer.{{cite news|url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm250168.htm|title=FDA approves new treatment for rare form of thyroid cancer|access-date=7 April 2011|archive-date=10 April 2011|archive-url=https://web.archive.org/web/20110410130203/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm250168.htm|url-status=dead}}

Vandetanib was first initially marketed without a trade name; it has been marketed under the trade name Caprelsa since August 2011.{{cite news| vauthors = Starkey J |title=AstraZeneca (finally) lands name for cancer drug|url=http://blogs.delawareonline.com/delawareinc/2011/08/02/astrazeneca-finally-lands-name-for-cancer-drug/|work=Delaware Inc.|date=August 2, 2011}}

In 2015 Genzyme acquired the product from AstraZeneca.{{cite news| vauthors = Fourcade M |title=Sanofi to Buy Caprelsa Drug from AstraZeneca for $300 Million|url=https://www.bloomberg.com/news/articles/2015-07-27/sanofi-to-buy-caprelsa-drug-from-astrazeneca-for-300-million|work=Bloomberg|date=27 July 2015}}

AstraZeneca tested Vandetanib in clinical trials for non-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.{{cite web|url=http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/001194/wapp/Initial_authorisation/human_wapp_000025.jsp&murl=menus/medicines/medicines.jsp&mid=WC0b01ac058001d128&jsenabled=true|title=Zactima|date=17 September 2018|publisher=European Medicines Agency|access-date=2 December 2010|archive-date=20 September 2018|archive-url=https://web.archive.org/web/20180920141748/http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fmedicines%2Fhuman%2Fmedicines%2F001194%2Fwapp%2FInitial_authorisation%2Fhuman_wapp_000025.jsp&murl=menus%2Fmedicines%2Fmedicines.jsp&mid=WC0b01ac058001d128&jsenabled=true|url-status=dead}} A clinical trial of vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma was negative in a prospective, randomised, double-blind, multicentre phase 2 trial.{{cite journal | vauthors = Middleton G, Palmer DH, Greenhalf W, Ghaneh P, Jackson R, Cox T, Evans A, Shaw VE, Wadsley J, Valle JW, Propper D, Wasan H, Falk S, Cunningham D, Coxon F, Ross P, Madhusudan S, Wadd N, Corrie P, Hickish T, Costello E, Campbell F, Rawcliffe C, Neoptolemos JP | title = Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma (ViP): a prospective, randomised, double-blind, multicentre phase 2 trial | journal = The Lancet. Oncology | volume = 18 | issue = 4 | pages = 486–499 | date = April 2017 | pmid = 28259610 | doi = 10.1016/S1470-2045(17)30084-0 | s2cid = 46676794 | url = http://eprints.nottingham.ac.uk/43057/ }}

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