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Identification
NameCabozantinib
Accession NumberDB08875
TypeSmall Molecule
GroupsApproved
Description

Cabozantinib was approved in 2012 and is a non-specific tyrosine kinase inhibitor. It is marketed as COMETRIQ™, which is indicated for the treatment of metastatic medullary thyroid cancer. It’s label includes a black box warning of gastrointestinal perforations, fistulas, and hemorrhage.

Structure
Thumb
Synonyms
SynonymLanguageCode
BMS 907351Not AvailableNot Available
BMS907351Not AvailableNot Available
Cabozantinib (S)-malateNot AvailableNot Available
Cabozantinib L-malateNot AvailableNot Available
cabozantinib s-malateNot AvailableNot Available
CometriqNot AvailableNot Available
XL 184Not AvailableNot Available
XL-184Not AvailableNot Available
XL184Not AvailableNot Available
SaltsNot Available
Brand names
NameCompany
COMETRIQEXELIXIS
Brand mixturesNot Available
CategoriesNot Available
CAS number849217-68-1
WeightNot Available
Chemical FormulaNot Available
InChI KeyNot Available
InChINot Available
IUPAC NameNot Available
SMILESNot Available
Mass SpecNot Available
Taxonomy
KingdomNot Available
SuperclassNot Available
ClassNot Available
SubclassNot Available
Direct parentNot Available
Alternative parentsNot Available
SubstituentsNot Available
Classification descriptionNot Available
Pharmacology
IndicationFor the treatment of metastatic medullary thyroid cancer.
PharmacodynamicsCabozantinib suppresses metastasis, angiogenesis, and oncognesis by inhibiting receptor tyrosine kinases.
Mechanism of actionCabozantinib inhibits specific receptor tyrosine kinases such as VEGFR-1, -2 and -3, KIT, TRKB, FLT-3, AXL, RET, MET, and TIE-2.
AbsorptionAfter oral administration, peak plasma concentration was achieved in 2-5 hours.
Volume of distribution

The volume of distribution is 349L.

Protein bindingCabozantinib has extensive plasma protein binding (≥ 99.7%).
Metabolism

Cabozantinib is metabolized mostly by CYP3A4 and, to a minor extent, by CYP2C9. Both enzyme produce an N-oxide metabolite.

Route of eliminationCabozantinib is eliminated mostly by the feces (54%) and also by the urine (27%).
Half lifeCabozantinib has a long half-life of 55 hours.
Clearance

At steady state, the clearance is 4.4 L/hr.

ToxicityCabozantinib has a black box warning of serious gastrointestinal fistulas and perforations, and potentially fatal hemoptysis and gastrointestinal hemorrhage.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption Not Available Not Available
Blood Brain Barrier Not Available Not Available
Caco-2 permeable Not Available Not Available
P-glycoprotein substrate Not Available Not Available
P-glycoprotein inhibitor I Not Available Not Available
P-glycoprotein inhibitor II Not Available Not Available
Renal organic cation transporter Not Available Not Available
CYP450 2C9 substrate Not Available Not Available
CYP450 2D6 substrate Not Available Not Available
CYP450 3A4 substrate Not Available Not Available
CYP450 1A2 substrate Not Available Not Available
CYP450 2C9 substrate Not Available Not Available
CYP450 2D6 substrate Not Available Not Available
CYP450 2C19 substrate Not Available Not Available
CYP450 3A4 substrate Not Available Not Available
CYP450 inhibitory promiscuity Not Available Not Available
Ames test Not Available Not Available
Carcinogenicity Not Available Not Available
Biodegradation Not Available Not Available
Rat acute toxicity Not Available Not applicable
hERG inhibition (predictor I) Not Available Not Available
hERG inhibition (predictor II) Not Available Not Available
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
CapsuleOralEQ 20MG BASE
CapsuleOralEQ 80MG BASE
PricesNot Available
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
water solubilityCOMETRIQ is practically insoluble in water.From FDA label.
Predicted PropertiesNot Available
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General Reference
  1. Durante C, Russo D, Verrienti A, Filetti S: XL184 (cabozantinib) for medullary thyroid carcinoma. Expert Opin Investig Drugs. 2011 Mar;20(3):407-413. doi: 10.1517/13543784.2011.559163. Pubmed
External Links
ResourceLink
KEGG DrugD10062
ChEBI72317
ChEMBLCHEMBL2105717
RxListhttp://www.rxlist.com/cometriq-drug.htm
Drugs.comhttp://www.drugs.com/mtm/cabozantinib.html
WikipediaCabozantinib
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelshow(194 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
EtravirineCabozantinib, when used concomitantly with etravirine, may experience a decrease in serum concentration. It is recommended to avoid this combination if alternative are available. If concurrent use is not avoidable, it is recommended to increase the dosage of cabozantinib by 40mg (without exceeding 180mg/day).
St. John's WortAvoid combination. May decrease concentration of cabozantinib. Also avoid all other strong CYP3A4 inducers.
Food Interactions
  • Avoid grapefruit juice. Combination may increase levels of cabozantinib. Also avoid all other strong CYP3A4 inhibitors.

Targets

1. Hepatocyte growth factor receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Hepatocyte growth factor receptor P08581 Details

References:

  1. Kurzrock R, Sherman SI, Ball DW, Forastiere AA, Cohen RB, Mehra R, Pfister DG, Cohen EE, Janisch L, Nauling F, Hong DS, Ng CS, Ye L, Gagel RF, Frye J, Muller T, Ratain MJ, Salgia R: Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol. 2011 Jul 1;29(19):2660-6. doi: 10.1200/JCO.2010.32.4145. Epub 2011 May 23. Pubmed
  2. Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, Qian F, Chu F, Bentzien F, Cancilla B, Orf J, You A, Laird AD, Engst S, Lee L, Lesch J, Chou YC, Joly AH: Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011 Dec;10(12):2298-308. doi: 10.1158/1535-7163.MCT-11-0264. Epub 2011 Sep 16. Pubmed

2. Vascular endothelial growth factor receptor 2

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Vascular endothelial growth factor receptor 2 P35968 Details

References:

  1. Kurzrock R, Sherman SI, Ball DW, Forastiere AA, Cohen RB, Mehra R, Pfister DG, Cohen EE, Janisch L, Nauling F, Hong DS, Ng CS, Ye L, Gagel RF, Frye J, Muller T, Ratain MJ, Salgia R: Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol. 2011 Jul 1;29(19):2660-6. doi: 10.1200/JCO.2010.32.4145. Epub 2011 May 23. Pubmed
  2. Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, Qian F, Chu F, Bentzien F, Cancilla B, Orf J, You A, Laird AD, Engst S, Lee L, Lesch J, Chou YC, Joly AH: Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011 Dec;10(12):2298-308. doi: 10.1158/1535-7163.MCT-11-0264. Epub 2011 Sep 16. Pubmed

3. Proto-oncogene tyrosine-protein kinase receptor Ret

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Proto-oncogene tyrosine-protein kinase receptor Ret P07949 Details

References:

  1. Kurzrock R, Sherman SI, Ball DW, Forastiere AA, Cohen RB, Mehra R, Pfister DG, Cohen EE, Janisch L, Nauling F, Hong DS, Ng CS, Ye L, Gagel RF, Frye J, Muller T, Ratain MJ, Salgia R: Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol. 2011 Jul 1;29(19):2660-6. doi: 10.1200/JCO.2010.32.4145. Epub 2011 May 23. Pubmed

Enzymes

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: no

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

From FDA label.


2. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: no

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

References:

From FDA label.


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Drug created on May 12, 2013 18:12 / Updated on May 12, 2013 21:27