Axitinib

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Axitinib
Axitinib2DACS.svg
Names
Trade namesInlyta, Axinix
Other namesAG013736
  • N-Methyl-2-[[3-[(E)-2-pyridin-2-ylethenyl]-1H-indazol-6-yl]sulfanyl]benzamide
Clinical data
Drug classTyrosine kinase inhibitor[1]
Main usesRenal cell cancer (RCC)[2]
Side effectsDiarrhea, high blood pressure, tiredness, nausea, weight loss, weakness, constipation[2]
Pregnancy
category
  • AU: D
Routes of
use
By mouth
Typical dose5 mg BID[2]
External links
AHFS/Drugs.comMonograph
US NLMAxitinib
MedlinePlusa612017
Legal
License data
Legal status
Pharmacokinetics
Bioavailability58%[4]
Protein binding>99%[4]
MetabolismLiver (mostly CYP3A4/CYP3A5-mediated but with some contributions from CYP1A2, CYP2C19, UGT1A1)[4]
Elimination half-life2.5-6.1 hours[4]
ExcretionFeces (41%; 12% as unchanged drug), urine (23%)[4]
Chemical and physical data
FormulaC22H18N4OS
Molar mass386.47 g·mol−1
3D model (JSmol)
  • CNC(=O)c1ccccc1Sc4ccc3c(C=Cc2ccccn2)n[nH]c3c4
  • InChI=1S/C22H18N4OS/c1-23-22(27)18-7-2-3-8-21(18)28-16-10-11-17-19(25-26-20(17)14-16)12-9-15-6-4-5-13-24-15/h2-14H,1H3,(H,23,27)(H,25,26)/b12-9+ checkY
  • Key:RITAVMQDGBJQJZ-FMIVXFBMSA-N checkY

Axitinib, sold under the brand name Inlyta, is a medication used to treat renal cell cancer (RCC).[2] It is used in advanced disease, either alone or with avelumab or pembrolizumab.[2] It increased time to getting worse to 6.7 months from 4.7 months in those taking sorafenib.[5] It is taken by mouth.[2]

Common side effects include diarrhea, high blood pressure, tiredness, nausea, weight loss, weakness, and constipation.[2] Other side effects may include blood clots, bleeding, heart failure, gastrointestinal perforation, low thyroid, poor wound healing, liver problems, and reversible posterior leukoencephalopathy syndrome (RPLS).[2] Use in pregnancy may harm the baby.[2] It is a tyrosine kinase inhibitor that blocks vascular endothelial growth factor (VEGF).[1]

Axitinib was approved for medical use in the United States and Europe in 2012.[5][2] In the United Kingdom 4 weeks of treatments costs the NHS about £3,500 as of 2021.[6] In the United States this amount costs about 17,300 USD.[7]

Medical uses

Renal cell cancer

It has received approval for use as a treatment for renal cell carcinoma from the US Food and Drug Administration (FDA) (27 January 2012), the European Medicines Agency (EMA) (13 September 2012), the UK Medicines and Healthcare products Regulatory Agency (MHRA) (3 September 2012) and the Australian Therapeutic Goods Administration (TGA) (26 July 2012).[3][8][9][10]

Dosage

It is take at a dose of 5 mg twice per day.[2] In those with moderate liver problems half that dose should be used.[2]

Side effects

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.[11]

Interactions

Coadministration with strong CYP3A4/CYP3A5 inhibitors should be avoided where possible as they may reduce plasma clearance of axitinib.[4]

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).[12]

It was also proposed that it might act by inducing autophagy, as some other tyrosine kinase inhibitors, like sorafenib.[13]

It has also been shown[14] 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
Protein IC50 (nM)
VEGFR1 0.1
VEGFR2 0.2
VEGFR3 0.1-0.3
PDGFR 1.6
c-KIT 1.7

Pharmacokinetics

Pharmacokinetic parameters of Axitinib[4]
Bioavailability Tmax Cmax AUC Vd Plasma protein binding Metabolising enzymes t1/2 Excretion routes
58% 2.5-4.1 hr 27.8 ng/mL 265 ng•h/mL 160 L >99% Mostly CYP3A4 and CYP3A5. Lesser contributions from CYP1A2, CYP2C19, UGT1A1 2.5-6.1 hr Faeces (41%), urine (23%)

Society and culture

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.

Research

A Phase II clinical trial showed good response in combination chemotherapy with gemcitabine for advanced pancreatic cancer.[15] 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.[16]

In 2010, a Phase III trial for previously treated metastatic renal cell carcinoma (mRCC) showed significantly extended progression-free survival when compared to sorafenib.[17] 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.[18]

It has also been studied in combination with the ALK1 inhibitor dalantercept.[19]

A study published in 2015[14] 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.

References

  1. 1.0 1.1 "Axitinib". LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Institute of Diabetes and Digestive and Kidney Diseases. 2012. Archived from the original on 6 May 2021. Retrieved 17 January 2022.
  2. 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 "DailyMed - INLYTA- axitinib tablet, film coated". dailymed.nlm.nih.gov. Archived from the original on 27 June 2021. Retrieved 17 January 2022.
  3. 3.0 3.1 "Inlyta- axitinib tablet, film coated". DailyMed. Pfizer Inc. Archived from the original on 27 November 2019. Retrieved 25 January 2014.
  4. 4.0 4.1 4.2 4.3 4.4 4.5 4.6 "Inlyta (axitinib) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 5 July 2018. Retrieved 25 January 2014.
  5. 5.0 5.1 "Inlyta". Archived from the original on 8 October 2021. Retrieved 17 January 2022.
  6. BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 1013. ISBN 978-0857114105.
  7. "Inlyta Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 19 April 2021. Retrieved 17 January 2022.
  8. "Inlyta : EPAR - Product Information" (PDF). European Medicines Agency. Pfizer Ltd. 17 December 2013. Archived (PDF) from the original on 5 July 2018. 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. Archived from the original on 29 March 2019. Retrieved 25 January 2014.
  11. "FDA Prescribing Information" (PDF). 30 Jan 2012. Archived (PDF) from the original on 25 February 2017. Retrieved 10 July 2021.
  12. 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.
  13. 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. Archived from the original on 2018-09-20. Retrieved 2021-07-10.
  14. 14.0 14.1 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.
  15. 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.
  16. "Pfizer pancreatic cancer drug fails, trial halted". Reuters. January 30, 2009. Archived from the original on February 14, 2009. Retrieved July 10, 2021.
  17. "Pfizer's Phase III Trial in mRCC Turns Up Positive Results". 19 Nov 2010. Archived from the original on 20 February 2018. Retrieved 10 July 2021.
  18. "ODAC Unanimously Supports Axitinib for Renal Cell Carcinoma". 7 Dec 2011. Archived from the original on 5 April 2018. Retrieved 10 July 2021.
  19. "ALK1/VEGF Combo Active in Advanced RCC. Jan 2017". Archived from the original on 2017-02-02. Retrieved 2021-07-10.

External links

External sites:
Identifiers: