Axitinib

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Axitinib
Clinical data
Trade namesInlyta, Axinix
Other namesAG013736
AHFS/Drugs.comMonograph
MedlinePlusa612017
License data
Pregnancy
category
  • AU: D
Routes of
administration		By mouth
ATC code
Legal status
Legal status
UGT1A1)[2]
Elimination half-life2.5-6.1 hours[2]
ExcretionFeces (41%; 12% as unchanged drug), urine (23%)[2]
Identifiers
  • N-Methyl-2-[[3-[(E)-2-pyridin-2-ylethenyl]-1H-indazol-6-yl]sulfanyl]benzamide
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
 ☒NcheckY (what is this?)  (verify)

Axitinib, sold under the brand name Inlyta, is a small molecule

xenograft) models[3] and has shown partial responses in clinical trials with renal cell carcinoma (RCC)[4] and several other tumour types.[5]

It was approved to treat renal cell carcinoma by the U.S. Food and Drug Administration after showing a modest increase in progression-free survival,[6] though there have been reports of fatal adverse effects.[7]

Approvals and indications

Renal cell carcinoma

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).[1][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

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

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.

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 and inducers should be avoided where possible as they may increase or reduce plasma exposure of axitinib, respectively. [18]

Mechanism of action

Its primary mechanism of action is thought to be

c-KIT and PDGFR inhibition, this, in turn, enables it to inhibit angiogenesis (the formation of new blood vessels by tumours).[19]

It was also proposed that it might act by inducing autophagy, as some other tyrosine kinase inhibitors, like sorafenib.[20]

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
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[2]
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
UGT1A1
 2.5-6.1 hr Faeces (41%), urine (23%)

Society and culture

Brand names

In Bangladesh it is under the trade name Axinix.[citation needed]

In Germany, Switzerland and other European countries it is available under the trade name Inlyta.[21][22]

References

  1. ^ a b "Inlyta- axitinib tablet, film coated". DailyMed. Pfizer Inc. Retrieved 25 January 2014.
  2. ^ a b c d e f "Inlyta (axitinib) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 25 January 2014.
  3. PMID 17371720
    .
  4. ^ 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.
  5. PMID 16027439
    .
  6. ^ "FDA Approves Inlyta for Advanced Renal Cell Carcinoma". Drugs.com. January 27, 2012.
  7. ^ Fauber J, Chu E (October 27, 2014). "The Slippery Slope: Is a Surrogate Endpoint Evidence of Efficacy?". MedPage Today.
  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. 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. Archived from the original on 20 February 2018. Retrieved 26 November 2010.
  14. ^ "ODAC Unanimously Supports Axitinib for Renal Cell Carcinoma". 7 Dec 2011.
  15. ^ "ALK1/VEGF Combo Active in Advanced RCC. Jan 2017". Archived from the original on 2017-02-02. Retrieved 2017-01-28.
  16. ^
    S2CID 4389086
    .
  17. ^ "FDA Prescribing Information" (PDF). 30 Jan 2012.
  18. ^ "FDA Prescribing Information" (PDF). 7 Feb 2024.
  19. PMID 21679004
    .
  20. PMID 24213221
    .
  21. ^ AHFS Patient Medication Information [Internet]. Bethesda (MD): American Society of Health-System Pharmacists, Inc.; c2022. Axitinib; [last revised 2020 August 15; cited 2022 March 28]; [about 5 p.]. Available from: https://medlineplus.gov/druginfo/meds/a612017.html
  22. ^ "Axitinib". PubChem. U.S. National Library of Medicine. Retrieved 2022-03-28.

External links

  • "Axitinib". Drug Information Portal. U.S. National Library of Medicine.
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