Axitinib

Axitinib (AG013736; trade name Inlyta) is a small molecule tyrosine kinase inhibitor developed by Pfizer. It has been shown to significantly inhibit growth of breast cancer in animal (xenograft) models[2] and has shown partial responses in clinical trials with renal cell carcinoma (RCC)[3] and several other tumour types.[4]

Axitinib
Clinical data
Trade namesInlyta, Axinix
AHFS/Drugs.comMonograph
MedlinePlusa612017
License data
Pregnancy
category
  • AU: D
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability58%[1]
Protein binding>99%[1]
MetabolismHepatic (mostly CYP3A4/CYP3A5-mediated but with some contributions from CYP1A2, CYP2C19, UGT1A1)[1]
Elimination half-life2.5-6.1 hours[1]
ExcretionFaeces (41%; 12% as unchanged drug), urine (23%)[1]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.166.384
Chemical and physical data
FormulaC22H18N4OS
Molar mass386.47 g·mol−1
3D model (JSmol)
 NY (what is this?)  (verify)

It was approved for RCC by the U.S. Food and Drug Administration after showing a modest increase in progression-free survival,[5] though there have been reports of fatal adverse effects.[6]

Approvals and indications

Renal cell carcinoma

It has received approval for use as a treatment for renal cell carcinoma from US FDA (27 January 2012), EMA (13 September 2012), UK MHRA (3 September 2012) and Australian TGA (26 July 2012) .[7][8][9][10]

Clinical trials

A Phase II clinical trial showed good response in combination chemotherapy with gemcitabine for advanced pancreatic cancer.[11] However, Pfizer reported on January 30, 2009 that Phase III clinical trials of the drug when used in combination with gemcitabine showed no evidence of improved survival rates over treatments using gemcitabine alone for advanced pancreatic cancer and halted the trial.[12]

In 2010, a Phase III trial for previously treated metastatic renal cell carcinoma (mRCC) showed significantly extended progression-free survival when compared to sorafenib.[13] In December 2011, the Oncologic Drugs Advisory Committee (ODAC) voted unanimously to recommend that US FDA approve axitinib for the second-line treatment of patients with advanced renal cell carcinoma (RCC), based on the results of the Phase III trial comparing axitinib and sorafenib.[14]

It has also been studied in combination with the ALK1 inhibitor dalantercept.[15]

A study published in 2015[16] showed that axitinib effectively inhibits a mutated gene (BCR-ABL1[T315I]) that is common in chronic myeloid leukemias and adult acute lymphoblastic leukemias which have become resistant to other tyrosine kinase inhibitors like imatinib. This is one of the first examples of a new indication for an existing drug being discovered by screening known drugs using a patient's own cells.

Contraindications

The only contraindication to axitinib is hypersensitivity to axitinib.[10]

Cautions include:[1]

  • Hypertension
  • Thromboembolic (both venous and arterial) events
  • Haemorrhagic events (including cerebral haemorrhage)
  • GI perforations and fistula
  • Thyroid function, it is advised that thyroid function is measured initially and then periodically during treatment with axitinib.
  • Stop treatment 24 hours prior to surgery due to potential clotting changes
  • Proteinuria, it is advised that proteinuria is monitored initially and then periodically during therapy
  • Elevated liver enzymes reported, it is advised that AST, ALT and bilirubin are regularly monitored during treatment with axitinib
  • Moderate hepatic impairment requires dose reduction

Adverse effects
See also: List of adverse effects of axitinib

Diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, hand-foot syndrome, weight decreased, vomiting, asthenia, and constipation are the most common side effects occurring in more than 20% of patients.[17]

Interactions

Coadministration with strong CYP3A4/CYP3A5 inhibitors should be avoided where possible as they may reduce plasma clearance of axitinib.[1]

Mechanism of action

Its primary mechanism of action is thought to be vascular endothelial growth factor receptor 1-3, c-KIT and PDGFR inhibition, this, in turn, enables it to inhibit angiogenesis (the formation of new blood vessels by tumours).[18]

It was also proposed that it might act by inducing autophagy, as some other tyrosine kinase inhibitors, like sorafenib.[19]

It has also been shown[16] to bind (in a different conformation from the VEGF binding) to the BCR-ABL fusion protein, specifically inhibiting the drug-resistant T315I mutant isoform.

The effect of axitinib on tyrosine kinases
ProteinIC50 (nM)
VEGFR10.1
VEGFR20.2
VEGFR30.1-0.3
PDGFR1.6
c-KIT1.7

Pharmacokinetics
Pharmacokinetic parameters of Axitinib[1]
BioavailabilityTmaxCmaxAUCVdPlasma protein bindingMetabolising enzymest1/2Excretion routes
58%2.5-4.1 hr27.8 ng/mL265 ng•h/mL160 L>99%Mostly CYP3A4 and CYP3A5. Lesser contributions from CYP1A2, CYP2C19, UGT1A12.5-6.1 hrFaeces (41%), urine (23%)

Brand names

In Bangladesh it is under the trade name Axinix.

In Germany, Switzerland and other European countries it is available under the trade name Inlyta.

References
  1. "Inlyta (axitinib) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 25 January 2014.
  2. Wilmes LJ, Pallavicini MG, Fleming LM, Gibbs J, Wang D, Li KL, et al. (April 2007). "AG-013736, a novel inhibitor of VEGF receptor tyrosine kinases, inhibits breast cancer growth and decreases vascular permeability as detected by dynamic contrast-enhanced magnetic resonance imaging". Magnetic Resonance Imaging. 25 (3): 319–27. doi:10.1016/j.mri.2006.09.041. PMID 17371720.
  3. Rini B, Rixe O, Bukowski R, Michaelson MD, Wilding G, Hudes G, et al. (June 2005). "AG-013736, a multi-target tyrosine kinase receptor inhibitor, demonstrates anti-tumor activity in a Phase 2 study of cytokine-refractory, metastatic renal cell cancer (RCC)". Journal of Clinical Oncology ASCO Annual Meeting Proceedings. 23 (16S): 4509. Archived from the original on 2014-01-26.
  4. Rugo HS, Herbst RS, Liu G, Park JW, Kies MS, Steinfeldt HM, et al. (August 2005). "Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results". Journal of Clinical Oncology. 23 (24): 5474–83. doi:10.1200/JCO.2005.04.192. PMID 16027439.
  5. "FDA Approves Inlyta for Advanced Renal Cell Carcinoma". Drugs.com. January 27, 2012.
  6. Fauber J, Chu E (Oct 27, 2014). "The Slippery Slope: Is a Surrogate Endpoint Evidence of Efficacy?". MedPage Today.
  7. "INLYTA (axitinib) tablet, film coated [Pfizer Laboratories Div Pfizer Inc]". DailyMed. Pfizer Laboratories Div Pfizer Inc. September 2013. Retrieved 25 January 2014.
  8. "Inlyta : EPAR - Product Information" (PDF). European Medicines Agency. Pfizer Ltd. 17 December 2013. Retrieved 25 January 2014.
  9. "Inlyta 1 mg 3mg, 5 mg & 7mg film-coated tablets - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Pfizer Limited. 5 December 2013. Archived from the original on 2014-02-22. Retrieved 25 January 2014.
  10. "PRODUCT INFORMATION INLYTA (axitinib)" (PDF). TGA eBusiness Services. Pfizer Australia Pty Ltd. 5 July 2013. Retrieved 25 January 2014.
  11. Spano JP, Chodkiewicz C, Maurel J, Wong R, Wasan H, Barone C, et al. (June 2008). "Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer: an open-label randomised phase II study". Lancet. 371 (9630): 2101–8. doi:10.1016/S0140-6736(08)60661-3. PMID 18514303. S2CID 11062859.
  12. "Pfizer pancreatic cancer drug fails, trial halted". Reuters. January 30, 2009.
  13. "Pfizer's Phase III Trial in mRCC Turns Up Positive Results". 19 Nov 2010.
  14. "ODAC Unanimously Supports Axitinib for Renal Cell Carcinoma". 7 Dec 2011.
  15. ALK1/VEGF Combo Active in Advanced RCC. Jan 2017
  16. Pemovska T, Johnson E, Kontro M, Repasky GA, Chen J, Wells P, et al. (March 2015). "Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation". Nature. 519 (7541): 102–5. Bibcode:2015Natur.519..102P. doi:10.1038/nature14119. PMID 25686603. S2CID 4389086.
  17. "FDA Prescribing Information" (PDF). 30 Jan 2012.
  18. Escudier B, Gore M (2011). "Axitinib for the management of metastatic renal cell carcinoma". Drugs in R&D. 11 (2): 113–26. doi:10.2165/11591240-000000000-00000. PMC 3585900. PMID 21679004.
  19. Zhang Y, Xue D, Wang X, Lu M, Gao B, Qiao X (January 2014). "Screening of kinase inhibitors targeting BRAF for regulating autophagy based on kinase pathways". Molecular Medicine Reports. 9 (1): 83–90. doi:10.3892/mmr.2013.1781. PMID 24213221.
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