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Vandetanib

From Wikipedia, the free encyclopedia
(Redirected fromCaprelsa)
Chemical compound

Pharmaceutical compound
Vandetanib
Clinical data
Trade namesCaprelsa
Other namesZD6474
AHFS/Drugs.comMonograph
MedlinePlusa611037
License data
Pregnancy
category
Routes of
administration
By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding90–96%
MetabolismCYP3A4,FMO1,FMO3
Eliminationhalf-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
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard(EPA)
ECHA InfoCard100.195.611Edit this at Wikidata
Chemical and physical data
FormulaC22H24BrFN4O2
Molar mass475.362 g·mol−1
3D model (JSmol)
  • 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) checkY
  • Key:UHTHHESEBZOYNR-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Vandetanib, sold under the brand nameCaprelsa, is ananti-cancer medication that is used for the treatment of certain tumours of thethyroid gland. It acts as akinase inhibitor of a number of cell receptors, mainly thevascular endothelial growth factor receptor, theepidermal growth factor receptor, and theRET-tyrosine kinase.[4][5] The drug was developed byAstraZeneca[2] who later sold the rights toSanofi in 2015.[6][7]

Medical use

[edit]

Vandetanib is used to treatmedullary thyroid cancer in adults who are ineligible for surgery.[2][8][9]

Contraindications

[edit]

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]

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 thecornea,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.[8]

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,[11] 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.[8]

Interactions

[edit]

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]

Pharmacology

[edit]

Vandetanib is an inhibitor ofvascular endothelial growth factor receptor-2,epidermal growth factor receptor, andRET tyrosine kinases. RET tyrosine kinases; it weakly inhibits vascular endothelial growth factor receptor-3.[8][13]

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]

History

[edit]

Vandetanib was approved by the FDA in April 2011, for treatment of late-stage thyroid cancer.[16]

Vandetanib was first initially marketed without a trade name; it has been marketed under the trade name Caprelsa since August 2011.[17]

In 2015 Genzyme acquired the product from AstraZeneca.[18]

Research

[edit]

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]

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. Retrieved22 Oct 2023.
  2. ^abcdef"Caprelsa- vandetanib tablet, film coated".DailyMed. 19 June 2020. Retrieved8 December 2020.
  3. ^"Caprelsa EPAR".European Medicines Agency (EMA). 17 February 2012. Retrieved26 September 2024.
  4. ^"Definition of vandetanib".NCI Drug Dictionary.National Cancer Institute. 2011-02-02.
  5. ^abcd"Vandetanib Monograph". Drugs.com. Retrieved29 August 2012.
  6. ^"AZ sells rare cancer drug to Sanofi".PMLive. 2015-07-27. Retrieved2021-01-26.
  7. ^"Genzyme to Buy Caprelsa from AstraZeneca for Up to $300M".GEN - Genetic Engineering and Biotechnology News. 2015-07-27. Retrieved2021-01-26.
  8. ^abcd"UK label".www.medicines.org.uk. UK Electronic Medicines Compendium. 16 December 2016. Archived fromthe original on 28 February 2017. Retrieved27 February 2017.
  9. ^abViola 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.
  10. ^abKhurana 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.
  11. ^Acitelli E, Maiorca C, Grani G, Maranghi M (July 2023)."Metabolic adverse events of multitarget kinase inhibitors: a systematic review".Endocrine.81 (1):16–29.doi:10.1007/s12020-023-03362-2.PMC 10239378.PMID 37067769.
  12. ^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.
  13. ^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.
  14. ^ab"Clinical Pharmacology Review: Vandetanib"(PDF). USFood and Drug Administration, Center for Drug Evaluation and Research. 20 August 2010. Retrieved29 August 2012.
  15. ^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.PMID 22206795.
  16. ^"FDA approves new treatment for rare form of thyroid cancer". Archived fromthe original on 10 April 2011. Retrieved7 April 2011.
  17. ^Starkey J (August 2, 2011)."AstraZeneca (finally) lands name for cancer drug".Delaware Inc.
  18. ^Fourcade M (27 July 2015)."Sanofi to Buy Caprelsa Drug from AstraZeneca for $300 Million".Bloomberg.
  19. ^"Zactima".European Medicines Agency. 17 September 2018. Archived fromthe original on 20 September 2018. Retrieved2 December 2010.
  20. ^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.
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