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Vandetanib

April 11, 2024

Vandetanib, sold under the brand name Caprelsa, is an anti-cancer medication that is used for the treatment of certain tumours of the thyroid gland. It acts as a kinase inhibitor of a number of cell receptors, mainly the vascular endothelial growth factor receptor (VEGFR), the epidermal growth factor receptor (EGFR), and the RET-tyrosine kinase.[3][4] The drug was developed by AstraZeneca[2] who later sold the rights to Sanofi in 2015.[5][6]

Vandetanib
Clinical data
Trade namesCaprelsa
Other namesZD6474
AHFS/Drugs.comMonograph
MedlinePlusa611037
License data
Pregnancy
category
  • AU: D
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding90–96%
MetabolismCYP3A4, FMO1, FMO3
Elimination half-life19 days (mean)[2]
Excretion44% faeces, 25% urine
Identifiers
  • N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine
CAS Number
  • 443913-73-3 N
PubChem CID
  • 3081361
IUPHAR/BPS
  • 5717
DrugBank
  • DB08764 Y
ChemSpider
  • 2338979 Y
UNII
  • YO460OQ37K
KEGG
  • D06407
ChEBI
  • CHEBI:49960 Y
ChEMBL
  • ChEMBL24828 Y
PDB ligand
  • ZD6 (PDBe, RCSB PDB)
CompTox Dashboard (EPA)
  • DTXSID1046681
ECHA InfoCard100.195.611
Chemical and physical data
FormulaC22H24BrFN4O2
Molar mass475.362 g·mol−1
3D model (JSmol)
  • Interactive image
  • CN1CCC(CC1)COc2cc3c(cc2OC)c(ncn3)Nc4ccc(cc4F)Br
  • InChI=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) Y
  • Key:UHTHHESEBZOYNR-UHFFFAOYSA-N Y
 NY (what is this?)  (verify)

Medical use edit

Vandetanib is used to treat medullary thyroid cancer in adults who are ineligible for surgery.[2][7][8]

Contraindications edit

The V804M mutation in RET confers resistance to Vandetanib anti-RET activity.[8]

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.[9] Vandetanib is contraindicated in people with congenital long QT syndrome.[2][4]

Adverse effects edit

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.[7]

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, 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.[7]

Interactions edit

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.[9] Also, vandetanib is an inhibitor of OATP1B3 transporter but not for OATP1B1.[10]

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.[2][4]

Pharmacology edit

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 VEGFR-3.[7][11]

 
Metabolites of vandetanib (top left): N-desmethylvandetanib (bottom left, via CYP3A4), vandetanib-N-oxide (bottom right, via FMO1 and FMO3), both pharmacologically active, and a minor amount of a glucuronide.[12]

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.[4][13][12]

History edit

Vandetanib was approved by the FDA in April 2011, for treatment of late-stage thyroid cancer.[14]

Vandetanib was first initially marketed without a trade name; it has been marketed under the trade name Caprelsa since August 2011.[15]

In 2015 Genzyme acquired the product from AstraZeneca.[16]

Research edit

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.[17] 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.[18]

References edit

  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
  2. ^ a b c d e f "Caprelsa- vandetanib tablet, film coated". DailyMed. 19 June 2020. Retrieved 8 December 2020.
  3. ^ "Definition of vandetanib". NCI Drug Dictionary. National Cancer Institute. 2011-02-02.
  4. ^ a b c d "Vandetanib Monograph". Drugs.com. Retrieved 29 August 2012.
  5. ^ "AZ sells rare cancer drug to Sanofi". PMLive. 2015-07-27. Retrieved 2021-01-26.
  6. ^ "Genzyme to Buy Caprelsa from AstraZeneca for Up to $300M". GEN - Genetic Engineering and Biotechnology News. 2015-07-27. Retrieved 2021-01-26.
  7. ^ a b c d . www.medicines.org.uk. UK Electronic Medicines Compendium. 16 December 2016. Archived from the original on 28 February 2017. Retrieved 27 February 2017.
  8. ^ a b Viola D, Valerio L, Molinaro E, Agate L, Bottici V, Biagini A, et al. (April 2016). "Treatment of advanced thyroid cancer with targeted therapies: ten years of experience". Endocrine-Related Cancer. 23 (4): R185–R205. doi:10.1530/ERC-15-0555. PMID 27207700.
  9. ^ a b Khurana V, Minocha M, Pal D, Mitra AK (March 2014). "Role of OATP-1B1 and/or OATP-1B3 in hepatic disposition of tyrosine kinase inhibitors". Drug Metabolism and Drug Interactions. 29 (3): 179–190. doi:10.1515/dmdi-2013-0062. PMC 4407685. PMID 24643910.
  10. ^ Khurana V, Minocha M, Pal D, Mitra AK (May 2014). "Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors". Drug Metabolism and Drug Interactions. 29 (4): 249–259. doi:10.1515/dmdi-2014-0014. PMC 4407688. PMID 24807167.
  11. ^ Carlomagno F, Vitagliano D, Guida T, Ciardiello F, Tortora G, Vecchio G, et al. (December 2002). "ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases". Cancer Research. 62 (24): 7284–7290. PMID 12499271.
  12. ^ a b "Clinical Pharmacology Review: Vandetanib" (PDF). US Food and Drug Administration, Center for Drug Evaluation and Research. 20 August 2010. Retrieved 29 August 2012.
  13. ^ Martin P, Oliver S, Kennedy SJ, Partridge E, Hutchison M, Clarke D, Giles P (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. PMID 22206795.
  14. ^ . Archived from the original on 10 April 2011. Retrieved 7 April 2011.
  15. ^ Starkey J (August 2, 2011). "AstraZeneca (finally) lands name for cancer drug". Delaware Inc.
  16. ^ Fourcade M (27 July 2015). "Sanofi to Buy Caprelsa Drug from AstraZeneca for $300 Million". Bloomberg.
  17. ^ "Zactima". European Medicines Agency. 17 September 2018.
  18. ^ Middleton G, Palmer DH, Greenhalf W, Ghaneh P, Jackson R, Cox T, et al. (April 2017). "Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma (ViP): a prospective, randomised, double-blind, multicentre phase 2 trial". The Lancet. Oncology. 18 (4): 486–499. doi:10.1016/S1470-2045(17)30084-0. PMID 28259610. S2CID 46676794.

External links edit

  • "Vandetanib". Drug Information Portal. U.S. National Library of Medicine.

April 11, 2024
vandetanib, sold, under, brand, name, caprelsa, anti, cancer, medication, that, used, treatment, certain, tumours, thyroid, gland, acts, kinase, inhibitor, number, cell, receptors, mainly, vascular, endothelial, growth, factor, receptor, vegfr, epidermal, grow. Vandetanib sold under the brand name Caprelsa is an anti cancer medication that is used for the treatment of certain tumours of the thyroid gland It acts as a kinase inhibitor of a number of cell receptors mainly the vascular endothelial growth factor receptor VEGFR the epidermal growth factor receptor EGFR and the RET tyrosine kinase 3 4 The drug was developed by AstraZeneca 2 who later sold the rights to Sanofi in 2015 5 6 VandetanibClinical dataTrade namesCaprelsaOther namesZD6474AHFS Drugs comMonographMedlinePlusa611037License dataEU EMA by INN US DailyMed Vandetanib US FDA VandetanibPregnancycategoryAU DRoutes ofadministrationBy mouthATC codeL01EX04 WHO Legal statusLegal statusAU S4 Prescription only CA only UK POM Prescription only US WARNING 1 Rx only 2 EU Rx onlyPharmacokinetic dataProtein binding90 96 MetabolismCYP3A4 FMO1 FMO3Elimination half life19 days mean 2 Excretion44 faeces 25 urineIdentifiersIUPAC name N 4 bromo 2 fluorophenyl 6 methoxy 7 1 methylpiperidin 4 yl methoxy quinazolin 4 amineCAS Number443913 73 3 NPubChem CID3081361IUPHAR BPS5717DrugBankDB08764 YChemSpider2338979 YUNIIYO460OQ37KKEGGD06407ChEBICHEBI 49960 YChEMBLChEMBL24828 YPDB ligandZD6 PDBe RCSB PDB CompTox Dashboard EPA DTXSID1046681ECHA InfoCard100 195 611Chemical and physical dataFormulaC 22H 24Br F N 4O 2Molar mass475 362 g mol 13D model JSmol Interactive imageSMILES CN1CCC CC1 COc2cc3c cc2OC c ncn3 Nc4ccc cc4F BrInChI InChI 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 YKey UHTHHESEBZOYNR UHFFFAOYSA N Y N Y what is this verify Contents 1 Medical use 2 Contraindications 3 Adverse effects 4 Interactions 5 Pharmacology 6 History 7 Research 8 References 9 External linksMedical use editVandetanib is used to treat medullary thyroid cancer in adults who are ineligible for surgery 2 7 8 Contraindications editThe V804M mutation in RET confers resistance to Vandetanib anti RET activity 8 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 9 Vandetanib is contraindicated in people with congenital long QT syndrome 2 4 Adverse effects editVery 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 7 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 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 7 Interactions editVandetanib 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 9 Also vandetanib is an inhibitor of OATP1B3 transporter but not for OATP1B1 10 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 2 4 Pharmacology editVandetanib is an inhibitor of vascular endothelial growth factor receptor 2 epidermal growth factor receptor and RET tyrosine kinases RET tyrosine kinases it weakly inhibits VEGFR 3 7 11 nbsp Metabolites of vandetanib top left N desmethylvandetanib bottom left via CYP3A4 vandetanib N oxide bottom right via FMO1 and FMO3 both pharmacologically active and a minor amount of a glucuronide 12 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 4 13 12 History editVandetanib was approved by the FDA in April 2011 for treatment of late stage thyroid cancer 14 Vandetanib was first initially marketed without a trade name it has been marketed under the trade name Caprelsa since August 2011 15 In 2015 Genzyme acquired the product from AstraZeneca 16 Research editAstraZeneca 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 17 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 18 References edit FDA sourced list of all drugs with black box warnings Use Download Full Results and View Query links nctr crs fda gov FDA Retrieved 22 Oct 2023 a b c d e f Caprelsa vandetanib tablet film coated DailyMed 19 June 2020 Retrieved 8 December 2020 Definition of vandetanib NCI Drug Dictionary National Cancer Institute 2011 02 02 a b c d Vandetanib Monograph Drugs com Retrieved 29 August 2012 AZ sells rare cancer drug to Sanofi PMLive 2015 07 27 Retrieved 2021 01 26 Genzyme to Buy Caprelsa from AstraZeneca for Up to 300M GEN Genetic Engineering and Biotechnology News 2015 07 27 Retrieved 2021 01 26 a b c d UK label www medicines org uk UK Electronic Medicines Compendium 16 December 2016 Archived from the original on 28 February 2017 Retrieved 27 February 2017 a b Viola D Valerio L Molinaro E Agate L Bottici V Biagini A et al April 2016 Treatment of advanced thyroid cancer with targeted therapies ten years of experience Endocrine Related Cancer 23 4 R185 R205 doi 10 1530 ERC 15 0555 PMID 27207700 a b Khurana V Minocha M Pal D Mitra AK March 2014 Role of OATP 1B1 and or OATP 1B3 in hepatic disposition of tyrosine kinase inhibitors Drug Metabolism and Drug Interactions 29 3 179 190 doi 10 1515 dmdi 2013 0062 PMC 4407685 PMID 24643910 Khurana V Minocha M Pal D Mitra AK May 2014 Inhibition of OATP 1B1 and OATP 1B3 by tyrosine kinase inhibitors Drug Metabolism and Drug Interactions 29 4 249 259 doi 10 1515 dmdi 2014 0014 PMC 4407688 PMID 24807167 Carlomagno F Vitagliano D Guida T Ciardiello F Tortora G Vecchio G et al December 2002 ZD6474 an orally available inhibitor of KDR tyrosine kinase activity efficiently blocks oncogenic RET kinases Cancer Research 62 24 7284 7290 PMID 12499271 a b Clinical Pharmacology Review Vandetanib PDF US Food and Drug Administration Center for Drug Evaluation and Research 20 August 2010 Retrieved 29 August 2012 Martin P Oliver S Kennedy SJ Partridge E Hutchison M Clarke D Giles P 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 PMID 22206795 FDA approves new treatment for rare form of thyroid cancer Archived from the original on 10 April 2011 Retrieved 7 April 2011 Starkey J August 2 2011 AstraZeneca finally lands name for cancer drug Delaware Inc Fourcade M 27 July 2015 Sanofi to Buy Caprelsa Drug from AstraZeneca for 300 Million Bloomberg Zactima European Medicines Agency 17 September 2018 Middleton G Palmer DH Greenhalf W Ghaneh P Jackson R Cox T et al April 2017 Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma ViP a prospective randomised double blind multicentre phase 2 trial The Lancet Oncology 18 4 486 499 doi 10 1016 S1470 2045 17 30084 0 PMID 28259610 S2CID 46676794 External links edit Vandetanib Drug Information Portal U S National Library of Medicine Portal nbsp Medicine Retrieved from https en wikipedia org w index php title Vandetanib amp oldid 1190943153, wikipedia, wiki, book, books, library,

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