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Identification
NameAxitinib
Accession NumberDB06626
TypeSmall Molecule
GroupsApproved, Investigational
Description

Axitinib is an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3. Axitinib is marketed under the name Inlyta®, and if one previous systemic therapy for kidney cell cancer has failed, axitinib is indicated.

Structure
Thumb
Synonyms
SynonymLanguageCode
SID103905539Not AvailableNot Available
SaltsNot Available
Brand names
NameCompany
InlytaPfizer
Brand mixturesNot Available
CategoriesNot Available
CAS number319460-85-0
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
IndicationUsed in kidney cell cancer and investigated for use/treatment in pancreatic and thyroid cancer.
PharmacodynamicsAxitinib prevents the progression of cancer by inhibiting angiogenesis and blocking tumor growth.
Mechanism of actionAxitinib selectively blocks the tyrosine kinase receptors VEGFR-1 (vascular endothelial growth factor receptor), VEGFR-2, and VEGFR-3.
AbsorptionAfter one 5 mg dose of axitinib, it takes about 2.5 to 4.1 hours to reach maximum plasma concentration.
Volume of distribution

The volume of distribution is 160 L.

Protein bindingPlasma protein binding for axitinib is high at over 99% with most protein binding to albumin followed by α1-acid glycoprotein.
Metabolism

Axitinib undergoes mainly hepatic metabolism. CYP3A4 and CYP3A5 are the main hepatic enzymes while CYP1A2, CYP2C19, and UGT1A1 enzymes are secondary.

Route of eliminationAxitinib is mainly eliminated unchanged in the feces (41%) with 12% of the original dose as unchanged axitinib. There is also 23% eliminated in the urine, most of which are metabolites.
Half lifeAxitinib has a half life of 2.5 to 6.1 hours.
Clearance

The average clearance of axitinib is 38 L/h.

ToxicitySome of the more serious toxic effects seen in patients taking axitinib include, but are not limited to, hypertension, thrombotic events, hemorrhage, and GI perforation.
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
TabletOral1 MG
TabletOral5 MG
PricesNot Available
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
water solubilityIn aqueous media with a pH between 1.1 to 7.8, axitinib has a solubility of over 0.2 μg/mL. From FDA label.
pKa4.8From FDA label.
Predicted PropertiesNot Available
Spectra
SpectraNot Available
References
Synthesis Reference

Hu-Lowe D, Hallin M, Feeley R, Zou H, Rewolinski D, Wickman G, Chen E, Kim Y, Riney S, Reed J, Heller D, Simmons B, Kania R, McTigue M, Niesman M, Gregory S, Shalinsky D, Bender S. Characterization of potency and activity of the VEGF/PDGF receptor tyrosine kinase inhibitor AG013736. Proc Am Assoc Cancer Res. 2002;43:A5357.

General Reference
  1. Cohen EE, Rosen LS, Vokes EE, Kies MS, Forastiere AA, Worden FP, Kane MA, Sherman E, Kim S, Bycott P, Tortorici M, Shalinsky DR, Liau KF, Cohen RB: Axitinib Is an Active Treatment for All Histologic Subtypes of Advanced Thyroid Cancer: Results From a Phase II Study. J Clin Oncol. 2008 Jun 9. Pubmed
  2. Inai T, Mancuso M, Hashizume H, Baffert F, Haskell A, Baluk P, Hu-Lowe DD, Shalinsky DR, Thurston G, Yancopoulos GD, McDonald DM: Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol. 2004 Jul;165(1):35-52. Pubmed
  3. Rugo HS, Herbst RS, Liu G, Park JW, Kies MS, Steinfeldt HM, Pithavala YK, Reich SD, Freddo JL, Wilding G: Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. J Clin Oncol. 2005 Aug 20;23(24):5474-83. Epub 2005 Jul 18. Pubmed
  4. Rini BI: SU11248 and AG013736: current data and future trials in renal cell carcinoma. Clin Genitourin Cancer. 2005 Dec;4(3):175-80. Pubmed
  5. Gilbert JA, Adhikari LJ, Lloyd RV, Halfdanarson TR, Muders MH, Ames MM: Molecular markers for novel therapeutic strategies in pancreatic endocrine tumors. Pancreas. 2013 Apr;42(3):411-21. doi: 10.1097/MPA.0b013e31826cb243. Pubmed
  6. FDA label.
External Links
ResourceLink
KEGG DrugD03218
ChEBI66910
ChEMBLCHEMBL1289926
PharmGKBPA164924493
RxListhttp://www.rxlist.com/inlyta-drug.htm
Drugs.comhttp://www.drugs.com/mtm/axitinib.html
WikipediaAxitinib
ATC CodesL01XE17
AHFS Codes
  • 10:00
PDB EntriesNot Available
FDA labelshow(307 KB)
MSDSshow(36.8 KB)
Interactions
Drug Interactions
Drug
ClobazamClobazam decreases levels by affecting CYP3A4 metabolism. Consider alternate therapy.
EtravirineAxitinib, when administered concomitantly with etravirine, may experience a decrease in serum concentrations. Recommended to avoid use of this combination.
PaclitaxelAvoid combination due to potential for decrease in serum concentration of axitinib.
PerampanelAvoid combination with axitinib or other major CYP3A4 drug susbtrates due to the potential decrease in the drug's concentration by perampanel induction of CYP3A4.
PhenytoinAvoid combination with phenytoin and other strong, moderate, or weak CYP3A4 inducers due to the likely decreased levels of axitinib.
St. John's WortAvoid combination due to the likely decreased levels of axitinib.
Food Interactions
  • Avoid combination with strong CYP3A4 inhibitors such as grapefruit juice due to the likely increased levels of axitinib. If the combination cannot be avoided, reduce axitinib dose by 50%.
  • Axitinib can be taken with or without food.

Targets

1. Vascular endothelial growth factor receptor 1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Vascular endothelial growth factor receptor 1 P17948 Details

References:

  1. Cohen EE, Rosen LS, Vokes EE, Kies MS, Forastiere AA, Worden FP, Kane MA, Sherman E, Kim S, Bycott P, Tortorici M, Shalinsky DR, Liau KF, Cohen RB: Axitinib Is an Active Treatment for All Histologic Subtypes of Advanced Thyroid Cancer: Results From a Phase II Study. J Clin Oncol. 2008 Jun 9. Pubmed

2. Vascular endothelial growth factor receptor 2

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

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

References:

  1. Cohen EE, Rosen LS, Vokes EE, Kies MS, Forastiere AA, Worden FP, Kane MA, Sherman E, Kim S, Bycott P, Tortorici M, Shalinsky DR, Liau KF, Cohen RB: Axitinib Is an Active Treatment for All Histologic Subtypes of Advanced Thyroid Cancer: Results From a Phase II Study. J Clin Oncol. 2008 Jun 9. Pubmed

3. Vascular endothelial growth factor receptor 3

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Vascular endothelial growth factor receptor 3 P35916 Details

References:

  1. Cohen EE, Rosen LS, Vokes EE, Kies MS, Forastiere AA, Worden FP, Kane MA, Sherman E, Kim S, Bycott P, Tortorici M, Shalinsky DR, Liau KF, Cohen RB: Axitinib Is an Active Treatment for All Histologic Subtypes of Advanced Thyroid Cancer: Results From a Phase II Study. J Clin Oncol. 2008 Jun 9. 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:

  1. Brennan M, Williams JA, Chen Y, Tortorici M, Pithavala Y, Liu YC: Meta-analysis of contribution of genetic polymorphisms in drug-metabolizing enzymes or transporters to axitinib pharmacokinetics. Eur J Clin Pharmacol. 2012 May;68(5):645-55. doi: 10.1007/s00228-011-1171-8. Epub 2011 Dec 15. Pubmed
  2. Chen Y, Tortorici MA, Garrett M, Hee B, Klamerus KJ, Pithavala YK: Clinical Pharmacology of Axitinib. Clin Pharmacokinet. 2013 May 16. Pubmed

2. Cytochrome P450 3A5

Kind: protein

Organism: Human

Pharmacological action: no

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A5 P20815 Details

References:

  1. Brennan M, Williams JA, Chen Y, Tortorici M, Pithavala Y, Liu YC: Meta-analysis of contribution of genetic polymorphisms in drug-metabolizing enzymes or transporters to axitinib pharmacokinetics. Eur J Clin Pharmacol. 2012 May;68(5):645-55. doi: 10.1007/s00228-011-1171-8. Epub 2011 Dec 15. Pubmed
  2. Chen Y, Tortorici MA, Garrett M, Hee B, Klamerus KJ, Pithavala YK: Clinical Pharmacology of Axitinib. Clin Pharmacokinet. 2013 May 16. Pubmed

3. Cytochrome P450 1A2

Kind: protein

Organism: Human

Pharmacological action: no

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 1A2 P05177 Details

References:

  1. Brennan M, Williams JA, Chen Y, Tortorici M, Pithavala Y, Liu YC: Meta-analysis of contribution of genetic polymorphisms in drug-metabolizing enzymes or transporters to axitinib pharmacokinetics. Eur J Clin Pharmacol. 2012 May;68(5):645-55. doi: 10.1007/s00228-011-1171-8. Epub 2011 Dec 15. Pubmed
  2. Chen Y, Tortorici MA, Garrett M, Hee B, Klamerus KJ, Pithavala YK: Clinical Pharmacology of Axitinib. Clin Pharmacokinet. 2013 May 16. Pubmed

4. Cytochrome P450 2C19

Kind: protein

Organism: Human

Pharmacological action: no

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C19 P33261 Details

References:

  1. Brennan M, Williams JA, Chen Y, Tortorici M, Pithavala Y, Liu YC: Meta-analysis of contribution of genetic polymorphisms in drug-metabolizing enzymes or transporters to axitinib pharmacokinetics. Eur J Clin Pharmacol. 2012 May;68(5):645-55. doi: 10.1007/s00228-011-1171-8. Epub 2011 Dec 15. Pubmed
  2. Chen Y, Tortorici MA, Garrett M, Hee B, Klamerus KJ, Pithavala YK: Clinical Pharmacology of Axitinib. Clin Pharmacokinet. 2013 May 16. Pubmed

5. UDP-glucuronosyltransferase 1-1

Kind: protein

Organism: Human

Pharmacological action: no

Actions: substrate

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 1-1 P22309 Details

References:

  1. Brennan M, Williams JA, Chen Y, Tortorici M, Pithavala Y, Liu YC: Meta-analysis of contribution of genetic polymorphisms in drug-metabolizing enzymes or transporters to axitinib pharmacokinetics. Eur J Clin Pharmacol. 2012 May;68(5):645-55. doi: 10.1007/s00228-011-1171-8. Epub 2011 Dec 15. Pubmed
  2. Chen Y, Tortorici MA, Garrett M, Hee B, Klamerus KJ, Pithavala YK: Clinical Pharmacology of Axitinib. Clin Pharmacokinet. 2013 May 16. Pubmed

Transporters

1. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: no

Actions: substrate

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

References:

  1. Brennan M, Williams JA, Chen Y, Tortorici M, Pithavala Y, Liu YC: Meta-analysis of contribution of genetic polymorphisms in drug-metabolizing enzymes or transporters to axitinib pharmacokinetics. Eur J Clin Pharmacol. 2012 May;68(5):645-55. doi: 10.1007/s00228-011-1171-8. Epub 2011 Dec 15. Pubmed
  2. Chen Y, Tortorici MA, Garrett M, Hee B, Klamerus KJ, Pithavala YK: Clinical Pharmacology of Axitinib. Clin Pharmacokinet. 2013 May 16. Pubmed

2. Solute carrier organic anion transporter family member 1B1

Kind: protein

Organism: Human

Pharmacological action: no

Actions: substrate

Components

Name UniProt ID Details
Solute carrier organic anion transporter family member 1B1 Q9Y6L6 Details

References:

  1. Brennan M, Williams JA, Chen Y, Tortorici M, Pithavala Y, Liu YC: Meta-analysis of contribution of genetic polymorphisms in drug-metabolizing enzymes or transporters to axitinib pharmacokinetics. Eur J Clin Pharmacol. 2012 May;68(5):645-55. doi: 10.1007/s00228-011-1171-8. Epub 2011 Dec 15. Pubmed

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Drug created on March 19, 2008 10:41 / Updated on May 28, 2013 20:50