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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
BMS 907351
BMS907351
Cabozantinib (S)-malate
Cabozantinib L-malate
cabozantinib s-malate
Cometriq
XL 184
XL-184
XL184
External Identifiers Not Available
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
CometriqkitExelixis, Inc.2012-11-29Not applicableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Cometriqcapsule20 mg/1oralExelixis, Inc.2012-11-29Not applicableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Cometriqcapsule20 mg/1oralExelixis, Inc.2012-11-29Not applicableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
CometriqkitExelixis, Inc.2012-11-29Not applicableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
CategoriesNot Available
CAS number849217-68-1
WeightNot Available
Chemical FormulaNot Available
InChI KeyNot Available
InChINot Available
IUPAC NameNot Available
SMILESNot Available
Taxonomy
ClassificationNot classified
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
PropertyValueProbability
Human Intestinal AbsorptionNot AvailableNot Available
Blood Brain BarrierNot AvailableNot Available
Caco-2 permeableNot AvailableNot Available
P-glycoprotein substrateNot AvailableNot Available
P-glycoprotein inhibitor INot AvailableNot Available
P-glycoprotein inhibitor IINot AvailableNot Available
Renal organic cation transporterNot AvailableNot Available
CYP450 2C9 substrateNot AvailableNot Available
CYP450 2D6 substrateNot AvailableNot Available
CYP450 3A4 substrateNot AvailableNot Available
CYP450 1A2 substrateNot AvailableNot Available
CYP450 2C9 inhibitorNot AvailableNot Available
CYP450 2D6 inhibitorNot AvailableNot Available
CYP450 2C19 inhibitorNot AvailableNot Available
CYP450 3A4 inhibitorNot AvailableNot Available
CYP450 inhibitory promiscuityNot AvailableNot Available
Ames testNot AvailableNot Available
CarcinogenicityNot AvailableNot Available
BiodegradationNot AvailableNot Available
Rat acute toxicityNot AvailableNot applicable
hERG inhibition (predictor I)Not AvailableNot Available
hERG inhibition (predictor II)Not AvailableNot Available
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Capsuleoral20 mg/1
Kit
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
water solubilityCOMETRIQ is practically insoluble in water.From FDA label.
Predicted PropertiesNot Available
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
References
Synthesis ReferenceNot Available
General References
  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
ATC CodesL01XE26
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (194 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
AprepitantThe serum concentration of Cabozantinib can be increased when it is combined with Aprepitant.
AtazanavirThe serum concentration of Cabozantinib can be increased when it is combined with Atazanavir.
BexaroteneThe serum concentration of Cabozantinib can be decreased when it is combined with Bexarotene.
BoceprevirThe serum concentration of Cabozantinib can be increased when it is combined with Boceprevir.
BosentanThe serum concentration of Cabozantinib can be decreased when it is combined with Bosentan.
CarbamazepineThe serum concentration of Cabozantinib can be decreased when it is combined with Carbamazepine.
CeritinibThe serum concentration of Cabozantinib can be increased when it is combined with Ceritinib.
ClarithromycinThe serum concentration of Cabozantinib can be increased when it is combined with Clarithromycin.
CobicistatThe serum concentration of Cabozantinib can be increased when it is combined with Cobicistat.
ConivaptanThe serum concentration of Cabozantinib can be increased when it is combined with Conivaptan.
DabrafenibThe serum concentration of Cabozantinib can be decreased when it is combined with Dabrafenib.
DarunavirThe serum concentration of Cabozantinib can be increased when it is combined with Darunavir.
DasatinibThe serum concentration of Cabozantinib can be increased when it is combined with Dasatinib.
DeferasiroxThe serum concentration of Cabozantinib can be decreased when it is combined with Deferasirox.
DexamethasoneThe serum concentration of Cabozantinib can be decreased when it is combined with Dexamethasone.
EnzalutamideThe serum concentration of Cabozantinib can be decreased when it is combined with Enzalutamide.
FluconazoleThe metabolism of Cabozantinib can be decreased when combined with Fluconazole.
FosaprepitantThe serum concentration of Cabozantinib can be increased when it is combined with Fosaprepitant.
FosphenytoinThe serum concentration of Cabozantinib can be decreased when it is combined with Fosphenytoin.
Fusidic AcidThe serum concentration of Cabozantinib can be increased when it is combined with Fusidic Acid.
IdelalisibThe serum concentration of Cabozantinib can be increased when it is combined with Idelalisib.
IndinavirThe serum concentration of Cabozantinib can be increased when it is combined with Indinavir.
ItraconazoleThe serum concentration of Cabozantinib can be increased when it is combined with Itraconazole.
IvacaftorThe serum concentration of Cabozantinib can be increased when it is combined with Ivacaftor.
KetoconazoleThe serum concentration of Cabozantinib can be increased when it is combined with Ketoconazole.
LuliconazoleThe serum concentration of Cabozantinib can be increased when it is combined with Luliconazole.
MifepristoneThe serum concentration of Cabozantinib can be increased when it is combined with Mifepristone.
MitotaneThe serum concentration of Cabozantinib can be decreased when it is combined with Mitotane.
NefazodoneThe serum concentration of Cabozantinib can be increased when it is combined with Nefazodone.
NelfinavirThe serum concentration of Cabozantinib can be increased when it is combined with Nelfinavir.
NetupitantThe serum concentration of Cabozantinib can be increased when it is combined with Netupitant.
PalbociclibThe serum concentration of Cabozantinib can be increased when it is combined with Palbociclib.
PamidronateThe risk or severity of adverse effects can be increased when Cabozantinib is combined with Pamidronate.
PhenobarbitalThe serum concentration of Cabozantinib can be decreased when it is combined with Phenobarbital.
PhenytoinThe serum concentration of Cabozantinib can be decreased when it is combined with Phenytoin.
PosaconazoleThe serum concentration of Cabozantinib can be increased when it is combined with Posaconazole.
PrimidoneThe serum concentration of Cabozantinib can be decreased when it is combined with Primidone.
RifabutinThe serum concentration of Cabozantinib can be decreased when it is combined with Rifabutin.
RifampicinThe serum concentration of Cabozantinib can be decreased when it is combined with Rifampicin.
RifapentineThe serum concentration of Cabozantinib can be decreased when it is combined with Rifapentine.
RitonavirThe serum concentration of Cabozantinib can be increased when it is combined with Ritonavir.
SaquinavirThe serum concentration of Cabozantinib can be increased when it is combined with Saquinavir.
SiltuximabThe serum concentration of Cabozantinib can be decreased when it is combined with Siltuximab.
SimeprevirThe serum concentration of Cabozantinib can be increased when it is combined with Simeprevir.
St. John's WortThe serum concentration of Cabozantinib can be decreased when it is combined with St. John's Wort.
StiripentolThe serum concentration of Cabozantinib can be increased when it is combined with Stiripentol.
TelaprevirThe serum concentration of Cabozantinib can be increased when it is combined with Telaprevir.
TelithromycinThe serum concentration of Cabozantinib can be increased when it is combined with Telithromycin.
TocilizumabThe serum concentration of Cabozantinib can be decreased when it is combined with Tocilizumab.
VoriconazoleThe serum concentration of Cabozantinib can be increased when it is combined with Voriconazole.
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