Axitinib Explained

Axitinib, sold under the brand 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[1] and has shown partial responses in clinical trials with renal cell carcinoma (RCC)[2] and several other tumour types.[3]

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,[4] though there have been reports of fatal adverse effects.[5]

Medical uses

Renal cell carcinoma

It has received approval for use as a treatment for renal cell carcinoma from the US Food and Drug Administration (FDA) (January 2012), the European Medicines Agency (EMA) (September 2012), the UK Medicines and Healthcare products Regulatory Agency (MHRA) (September 2012) and the Australian Therapeutic Goods Administration (TGA) (July 2012).[6] [7] [8] [9]

Clinical trials

A Phase II clinical trial showed good response in combination chemotherapy with gemcitabine for advanced pancreatic cancer.[10] However, Pfizer reported on 30 January 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.[11]

In 2010, a Phase III trial for previously treated metastatic renal cell carcinoma (mRCC) showed significantly extended progression-free survival when compared to sorafenib.[12] 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.[13]

It has also been studied in combination with the ALK1 inhibitor dalantercept.[14]

A study published in 2015[15] 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.

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.[16]

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. [17]

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 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)
0.1
0.2
0.1-0.3
1.6
1.7

Pharmacokinetics

Metabolising enzymes !! t1/2 !! Excretion routes
58% 2.5-4.1 hr 27.8 ng/mL 265 ng•h/mL 160 L >99% 2.5-6.1 hr Faeces (41%), urine (23%)

Society and culture

Legal status

In July 2024, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Axitinib Accord, intended for the treatment of adults with renal cell carcinoma. The applicant for this medicinal product is Accord Healthcare S.L.U.[20]

Brand names

In the European Union, it is sold under the brand name Inlyta.

Notes and References

  1. Wilmes LJ, Pallavicini MG, Fleming LM, Gibbs J, Wang D, Li KL, Partridge SC, Henry RG, Shalinsky DR, Hu-Lowe D, Park JW, McShane TM, Lu Y, Brasch RC, Hylton NM . 6 . 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 . 319–327 . April 2007 . 17371720 . 10.1016/j.mri.2006.09.041 .
  2. Rini B, Rixe O, Bukowski R, Michaelson MD, Wilding G, Hudes G, Bolte O, Steinfeldt H, Reich SD, Motzer R . 6 . 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 . 4509 . 23 . 16S . https://archive.today/20140126111958/http://meeting.ascopubs.org/cgi/content/abstract/23/16_suppl/4509 . dead . 26 January 2014 .
  3. Rugo HS, Herbst RS, Liu G, Park JW, Kies MS, Steinfeldt HM, Pithavala YK, Reich SD, Freddo JL, Wilding G . 6 . 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 . 5474–5483 . August 2005 . 16027439 . 10.1200/JCO.2005.04.192 . free .
  4. Web site: FDA Approves Inlyta for Advanced Renal Cell Carcinoma . 27 January 2012 . Drugs.com.
  5. The Slippery Slope: Is a Surrogate Endpoint Evidence of Efficacy? . MedPage Today . 27 October 2014 . Fauber J, Chu E .
  6. Web site: Inlyta- axitinib tablet, film coated. DailyMed. Pfizer Inc.. 25 January 2014.
  7. Web site: Inlyta : EPAR - Product Information. European Medicines Agency. Pfizer Ltd.. 17 December 2013. 25 January 2014. 5 July 2018. https://web.archive.org/web/20180705092411/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002406/WC500132188.pdf. dead.
  8. Web site: Inlyta 1 mg 3mg, 5 mg & 7mg film-coated tablets - Summary of Product Characteristics (SPC). electronic Medicines Compendium. Pfizer Limited. 5 December 2013. 25 January 2014. https://web.archive.org/web/20140222203314/http://www.medicines.org.uk/emc/medicine/27051/SPC/Inlyta+1+mg+3mg%2C+5+mg+%26+7mg+film-coated+tablets/. 22 February 2014. dead.
  9. Web site: PRODUCT INFORMATION INLYTA (axitinib). TGA eBusiness Services. Pfizer Australia Pty Ltd.. 5 July 2013. 25 January 2014. PDF.
  10. Spano JP, Chodkiewicz C, Maurel J, Wong R, Wasan H, Barone C, Létourneau R, Bajetta E, Pithavala Y, Bycott P, Trask P, Liau K, Ricart AD, Kim S, Rixe O . 6 . 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 . 2101–2108 . June 2008 . 18514303 . 10.1016/S0140-6736(08)60661-3 . 11062859 .
  11. Web site: Pfizer pancreatic cancer drug fails, trial halted. 30 January 2009 . Reuters.
  12. News: Pfizer's Phase III Trial in mRCC Turns Up Positive Results . 19 November 2010 . 26 November 2010 . 20 February 2018 . https://web.archive.org/web/20180220092331/https://www.genengnews.com/gen-news-highlights/pfizer-s-phase-iii-trial-in-mrcc-turns-up-positive-results/81244271/ . dead .
  13. News: ODAC Unanimously Supports Axitinib for Renal Cell Carcinoma . 7 December 2011 .
  14. Web site: ALK1/VEGF Combo Active in Advanced RCC. Jan 2017 . 28 January 2017 . 2 February 2017 . https://web.archive.org/web/20170202084311/http://www.cancernetwork.com/renal-cell-carcinoma/alk1-vegf-combo-active-advanced-rcc . dead .
  15. Pemovska T, Johnson E, Kontro M, Repasky GA, Chen J, Wells P, Cronin CN, McTigue M, Kallioniemi O, Porkka K, Murray BW, Wennerberg K . 6 . Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation . Nature . 519 . 7541 . 102–105 . March 2015 . 25686603 . 10.1038/nature14119 . 4389086 . 2015Natur.519..102P .
  16. Web site: FDA Prescribing Information . 30 January 2012.
  17. Web site: FDA Prescribing Information . 7 February 2024.
  18. Escudier B, Gore M . Axitinib for the management of metastatic renal cell carcinoma . Drugs in R&D . 11 . 2 . 113–126 . 2011 . 21679004 . 3585900 . 10.2165/11591240-000000000-00000 .
  19. Zhang Y, Xue D, Wang X, Lu M, Gao B, Qiao X . Screening of kinase inhibitors targeting BRAF for regulating autophagy based on kinase pathways . Molecular Medicine Reports . 9 . 1 . 83–90 . January 2014 . 24213221 . 10.3892/mmr.2013.1781 . free .
  20. Web site: Axitinib Accord EPAR . European Medicines Agency . 25 July 2024 . 27 July 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

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