Vandetanib

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Vandetanib
Vandetanib2DACS.svg
Systematic (IUPAC) name
N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine
Clinical data
Trade names Caprelsa
AHFS/Drugs.com Consumer Drug Information
MedlinePlus a611037
Licence data US FDA:link
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
Legal status
Routes of
administration		 Oral
Pharmacokinetic data
Protein binding 90–96%
Metabolism CYP3A4, FMO1, FMO3
Biological half-life 19 days (mean)[1]
Excretion 44% faeces, 25% urine
Identifiers
CAS Number 443913-73-3 N
ATC code L01XE12 (WHO)
PubChem CID: 3081361
IUPHAR/BPS 5717
DrugBank DB08764 YesY
ChemSpider 2338979 YesY
UNII YO460OQ37K YesY
ChEBI CHEBI:49960 YesY
ChEMBL CHEMBL24828 YesY
Synonyms ZD6474
Chemical data
Formula C22H24BrFN4O2
Molecular mass 475.354 g/mol
  • 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) YesY
  • Key:UHTHHESEBZOYNR-UHFFFAOYSA-N YesY
 NYesY (what is this?)  (verify)

Vandetanib (INN, trade name Caprelsa) is an anti-cancer drug 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.[2][3] The drug was developed by AstraZeneca.

Approvals and indications

Vandetanib was the first drug to be approved by FDA (April 2011) for treatment of late-stage (metastatic) medullary thyroid cancer in adult patients who are ineligible for surgery.[4] Vandetanib was first initially marketed without a trade name,[5] and is being marketed under the trade name Caprelsa since August 2011.[6]

Contraindications

In patients with moderate and severe hepatic impairment, no dosage for vandetanib has been recommended, as its safety and efficacy has not been established yet.[7] Vandetanib is contraindicated in patients with congenital long QT syndrome.[3][8]

Adverse effects

Common side effects include abdominal pain and diarrhoea, rashes, prolonged QT interval, hypertension, headache, and fatigue.[3][8]

Interactions

Vandetanib has been reported as a substrate for the OATP-1B1 and OATP-1B3 transporter. Interaction of vandetanib with OATP-1B1 and OATP-1B3 may alter its hepatic disposition and can lead to transporter mediated drug-drug interactions.[7] Also, vandetanib is an inhibitor of OATP-1B3 transporter but not for OATP-1B1.[9]

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.[3][8]

Pharmacokinetics

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 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.[3][10][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.[11]

Clinical trials

Non-small cell lung cancer

The drug underwent clinical trials as a potential targeted treatment for non-small-cell lung cancer. There have been some promising results from a phase III trial with docetaxel.[12] There have also been ambivalent results when used with pemetrexed.[13] Another trial with docetaxel was recruiting in July 2009.[14]

AstraZeneca withdrew EU regulatory submissions for vandetanib (under the proposed trade name Zactima) in October 2009 after trials showed no benefit when the drug was administered alongside chemotherapy.[15]

References

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External links

  1. ↑ FDA Professional Drug Information for vandetanib
  2. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 Lua error in package.lua at line 80: module 'strict' not found.
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  8. ↑ 8.0 8.1 8.2 Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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  13. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ Clinical trial number NCT00687297 for "Study of Vandetanib Combined With Chemotherapy to Treat Advanced Non-small Cell Lung Cancer" at ClinicalTrials.gov
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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