Vandetanib

Last updated

Vandetanib
Vandetanib.svg
Clinical data
Trade names Caprelsa
Other namesZD6474
AHFS/Drugs.com Monograph
MedlinePlus a611037
License data
Pregnancy
category
  • AU:D
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding 90–96%
Metabolism CYP3A4, FMO1, FMO3
Elimination half-life 19 days (mean) [2]
Excretion 44% faeces, 25% urine
Identifiers
  • N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.195.611 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C22H24BrFN4O2
Molar mass 475.362 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) Yes check.svgY
  • Key:UHTHHESEBZOYNR-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

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, the epidermal growth factor receptor, 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]

Contents

Medical use

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

Contraindications

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

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, hypercholesterolemia, hypertriglyceridemia, [10] 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

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. [11]

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

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. [7] [12]

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. Vandetanib metabolism.svg
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.

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] [14] [13]

History

Vandetanib was approved by the FDA in April 2011, for treatment of late-stage thyroid cancer. [15]

Vandetanib was first initially marketed without a trade name; it has been marketed under the trade name Caprelsa since August 2011. [16]

In 2015 Genzyme acquired the product from AstraZeneca. [17]

Research

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. [18] 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. [19]

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References

  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. 1 2 3 4 5 6 "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. 1 2 3 4 "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. 1 2 3 4 "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.
  8. 1 2 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. 1 2 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. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. 1 2 "Clinical Pharmacology Review: Vandetanib" (PDF). US Food and Drug Administration, Center for Drug Evaluation and Research. 20 August 2010. Retrieved 29 August 2012.
  14. ↑ 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.
  15. ↑ "FDA approves new treatment for rare form of thyroid cancer". Archived from the original on 10 April 2011. Retrieved 7 April 2011.
  16. ↑ Starkey J (August 2, 2011). "AstraZeneca (finally) lands name for cancer drug". Delaware Inc.
  17. ↑ Fourcade M (27 July 2015). "Sanofi to Buy Caprelsa Drug from AstraZeneca for $300 Million". Bloomberg.
  18. ↑ "Zactima". European Medicines Agency. 17 September 2018.
  19. ↑ 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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