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Revision as of 15:48, 10 January 2012 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 465831867 of page Vandetanib for the Chem/Drugbox validation project (updated: 'CAS_number').  Latest revision as of 04:16, 26 September 2024 edit Whywhenwhohow (talk | contribs)Autopatrolled, Extended confirmed users, Pending changes reviewers49,153 edits infobox, links, refs 
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{{Short description|Chemical compound}}
{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Drugbox {{Drugbox
| Verifiedfields = changed | Verifiedfields = changed
| verifiedrevid = 410169887 | verifiedrevid = 470628961
⚫ | IUPAC_name = ''N''-(4-bromo-2-fluorophenyl)-6-methoxy-7-quinazolin-4-amine
| image = Vandetanib.svg | image = Vandetanib.svg
| alt =


<!--Clinical data--> <!-- Clinical data -->
| pronounce =
| tradename = Caprelsa | tradename = Caprelsa
| Drugs.com = {{drugs.com|CDI|vandetanib}} | Drugs.com = {{drugs.com|monograph|vandetanib}}
| MedlinePlus = a611037 | MedlinePlus = a611037
| licence_US = Vandetanib | DailyMedID = Vandetanib
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> | pregnancy_AU = D
| pregnancy_AU_comment =
| pregnancy_US = <!-- A / B / C / D / X -->
| pregnancy_category = | pregnancy_category=
⚫ | routes_of_administration = ]
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 -->
| class =
| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->
⚫ | ATC_prefix = L01
| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->
⚫ | ATC_suffix = EX04
| ATC_supplemental =

<!-- Legal status -->
| legal_AU = S4
| legal_CA = Rx-only
| legal_UK = POM
| legal_US = Rx-only | legal_US = Rx-only
| legal_US_comment = <ref name=USlabel />
| legal_status =
| legal_EU = Rx-only
⚫ | routes_of_administration = Oral
| legal_EU_comment = <ref name="Caprelsa EPAR">{{cite web | title=Caprelsa EPAR | website=European Medicines Agency (EMA) | date=17 February 2012 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/caprelsa | access-date=26 September 2024}}</ref>


<!--Pharmacokinetic data--> <!--Pharmacokinetic data-->
| bioavailability = | bioavailability =
| protein_bound = | protein_bound = 90–96%
| metabolism = | metabolism = ], ], ]
| elimination_half-life = 5 days (mean) | elimination_half-life = 19 days (mean)<ref name=USlabel/>
| excretion = | excretion = 44% faeces, 25% urine


<!--Identifiers--> <!--Identifiers-->
| IUPHAR_ligand = 5717
| CAS_number_Ref = {{cascite|correct|??}} | CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = <!-- blanked - oldvalue: 443913-73-3 --> | CAS_number = 443913-73-3
⚫ | ATC_prefix = L01
⚫ | ATC_suffix = XE12
| PubChem = 3081361 | PubChem = 3081361
| DrugBank_Ref = {{drugbankcite|changed|drugbank}} | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB08764 | DrugBank = DB08764
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 2338979 | ChemSpiderID = 2338979
| UNII_Ref = {{fdacite|changed|FDA}} | UNII_Ref = {{fdacite|correct|FDA}}
| UNII = YO460OQ37K | UNII = YO460OQ37K
| KEGG = D06407
| ChEBI_Ref = {{ebicite|changed|EBI}} | ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 49960 | ChEBI = 49960
| ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 24828 | ChEMBL = 24828
| PDB_ligand = ZD6
| synonyms = ZD6474


<!--Chemical data--> <!--Chemical data-->
⚫ | IUPAC_name = ''N''-(4-bromo-2-fluorophenyl)-6-methoxy-7-quinazolin-4-amine
| C=22 | H=24 | Br=1 | F=1 | N=4 | O=2 | C=22 | H=24 | Br=1 | F=1 | N=4 | O=2
| molecular_weight = 475.354 g/mol
| smiles = CN1CCC(CC1)COc2cc3c(cc2OC)c(ncn3)Nc4ccc(cc4F)Br | smiles = CN1CCC(CC1)COc2cc3c(cc2OC)c(ncn3)Nc4ccc(cc4F)Br
| InChI = 1/C22H24BrFN4O2/c1-28-7-5-14(6-8-28)12-30-21-11-19-16(10-20(21)29-2)22(26-13-25-19)27-18-4-3-15(23)9-17(18)24/h3-4,9-11,13-14H,5-8,12H2,1-2H3,(H,25,26,27)
| InChIKey = UHTHHESEBZOYNR-UHFFFAOYAR
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C22H24BrFN4O2/c1-28-7-5-14(6-8-28)12-30-21-11-19-16(10-20(21)29-2)22(26-13-25-19)27-18-4-3-15(23)9-17(18)24/h3-4,9-11,13-14H,5-8,12H2,1-2H3,(H,25,26,27) | StdInChI = 1S/C22H24BrFN4O2/c1-28-7-5-14(6-8-28)12-30-21-11-19-16(10-20(21)29-2)22(26-13-25-19)27-18-4-3-15(23)9-17(18)24/h3-4,9-11,13-14H,5-8,12H2,1-2H3,(H,25,26,27)
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| StdInChIKey = UHTHHESEBZOYNR-UHFFFAOYSA-N | StdInChIKey = UHTHHESEBZOYNR-UHFFFAOYSA-N
}} }}

'''Vandetanib''', sold under the brand name '''Caprelsa''', is an ] that is used for the treatment of certain tumours of the ]. It acts as a ] of a number of cell receptors, mainly the ], the ], and the ]-tyrosine kinase.<ref>{{cite web|url=https://www.cancer.gov/publications/dictionaries/cancer-drug?CdrID=269177|title=Definition of vandetanib|publisher=]|work=NCI Drug Dictionary|date=2011-02-02}}</ref><ref name="Drugs.com" /> The drug was developed by ]<ref name=USlabel/> who later sold the rights to ] in 2015.<ref>{{Cite web|date=2015-07-27|title=AZ sells rare cancer drug to Sanofi|url=http://www.pmlive.com/pharma_news/az_sells_rare_cancer_drug_to_sanofi_787519|access-date=2021-01-26|website=PMLive|language=en}}</ref><ref>{{Cite web|date=2015-07-27|title=Genzyme to Buy Caprelsa from AstraZeneca for Up to $300M|url=https://www.genengnews.com/news/genzyme-to-buy-caprelsa-from-astrazeneca-for-up-to-300m/|access-date=2021-01-26|website=GEN - Genetic Engineering and Biotechnology News|language=en-US}}</ref>

==Medical use==
Vandetanib is used to treat ] in adults who are ineligible for surgery.<ref name=USlabel>{{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}}</ref><ref name=UKlabel>{{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}}</ref><ref name=Viola2016rev>{{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 }}</ref>

==Contraindications==
The V804M mutation in ] confers resistance to Vandetanib anti-RET activity.<ref name=Viola2016rev/>

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.<ref name="pmid24643910">{{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 }}</ref> Vandetanib is contraindicated in people with congenital ].<ref name=USlabel/><ref name="Drugs.com">{{cite web|publisher=Drugs.com|url=https://www.drugs.com/monograph/vandetanib.html|title=Vandetanib Monograph|access-date=29 August 2012}}</ref>

==Adverse effects==
Very common (present in greater than 10% of people) adverse effects include colds, bronchitis, upper respiratory tract infections, urinary tract infections, decreased appetite, ], insomnia, ], Headache, ], ], dizziness, blurred vision, damage to the ], ], high blood pressure, stomach pain, diarrhea, nausea, vomiting, indigestion, ], rash, acne, dry and itchy skin, nail disorders, ], kidney stones, weakness, fatigue, pain, and edema.<ref name=UKlabel/>

Common (present in between 1% and 10% of people) adverse effects include pneumonia, sepsis, influenza, cystitis, sinusitis, laryngitis, folliculitis, ], fungal infection, ], ], ], ], ], ], ],<ref>{{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 }}</ref> dehydration, ], anxiety, tremor, lethargy, loss of consciousness, balance disorders, ], visual impairment, halo vision, ], glaucoma, ], dry eye, keratopathy, ], ], nose bleeds, ], defecating blood, colitis, dry mouth, ], constipation, gastritis, ], ], hair loss, painful urination, bloody urine, ], frequent urination, urgent need to urinate, and fever.<ref name=UKlabel/>

== Interactions ==

Vandetanib has been reported as a substrate for the ] and ] transporters. Interaction of vandetanib with OATP1B1 and OATP1B3 may alter its hepatic disposition and can lead to transporter mediated drug-drug interactions.<ref name="pmid24643910"/> Also, vandetanib is an inhibitor of OATP1B3 transporter but not for OATP1B1.<ref name="Khurana V_2014">{{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 }}</ref>

Other drugs that ] can possibly add to this side effect of vandetanib. As the drug is partly metabolised via the liver enzyme ], strong ] can decrease its blood plasma concentrations. CYP3A4 inhibitors do not significantly increase vandetanib concentrations, presumably because it is also metabolised by ] (FMO1) and ].<ref name=USlabel/><ref name="Drugs.com" />

==Pharmacology==
Vandetanib is an inhibitor of ]-2, ], and ]. RET tyrosine kinases; it weakly inhibits vascular endothelial growth factor receptor-3.<ref name=UKlabel/><ref>{{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 }}</ref>

]), vandetanib-''N''-oxide (bottom right, via ] and ]), both pharmacologically active, and a minor amount of a ].<ref name="FDA"/>]]

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 ]. It is metabolised to ''N''-desmethylvandetanib via CYP3A4 and to vandetanib-''N''-oxide via FMO1 and 3. Both of these are ]s. Vandetanib is excreted via the faeces (44%) and the urine (25%) in form of the unchanged drug and the metabolites.<ref name="Drugs.com" /><ref>{{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 }}</ref><ref name="FDA">{{cite web|url=http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022405Orig1s000ClinPharmR.pdf|title=Clinical Pharmacology Review: Vandetanib|publisher=US ], Center for Drug Evaluation and Research|date=20 August 2010|access-date=29 August 2012}}</ref>

==History==
Vandetanib was approved by the FDA in April 2011, for treatment of late-stage thyroid cancer.<ref>{{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}}</ref>

Vandetanib was first initially marketed without a trade name; it has been marketed under the trade name Caprelsa since August 2011.<ref>{{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}}</ref>

In 2015 Genzyme acquired the product from AstraZeneca.<ref>{{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}}</ref>

==Research==
AstraZeneca tested Vandetanib in clinical trials for ] 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.<ref>{{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=]}}</ref> A clinical trial of vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic ] was negative in a prospective, randomised, double-blind, multicentre phase 2 trial.<ref>{{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/ }}</ref>

== References ==
{{reflist}}

{{Targeted cancer therapeutic agents}}
{{Growth factor receptor modulators}}
{{AstraZeneca}}
{{Portal bar | Medicine}}

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