|Systematic (IUPAC) name|
|Licence data||EMA: , US FDA:|
|Metabolism||Hepatic (mostly CYP3A4/CYP3A5-mediated but with some contributions from CYP1A2, CYP2C19, UGT1A1)|
|Excretion||Faeces (41%; 12% as unchanged drug), urine (23%)|
|PDB ligand ID||AXI (, )|
|14px (what is this?)|
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 and has shown partial responses in clinical trials with renal cell carcinoma (RCC) and several other tumour types. It was approved by the U.S. Food and Drug Administration after showing a modest increase in progression-free survival, though there have been reports of fatal adverse effects.
A Phase II clinical trial showed good response in combination chemotherapy with gemcitabine for advanced pancreatic cancer. 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.
In 2010, a Phase III trial for previously treated metastatic renal cell carcinoma (mRCC) showed significantly extended progression-free survival when compared to sorafenib. In December 2011, the Oncologic Drugs Advisory Committee (ODAC) voted unanimously to recommend the approval of 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.
A study published in 2015 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.
The only contraindication to axitinib is hypersensitivity to axitinib.
- 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
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.
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).
|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%)|
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- 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 (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. PMID 17371720. doi:10.1016/j.mri.2006.09.041.
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- John Fauber, Elbert Chu (Oct 27, 2014). "The Slippery Slope: Is a Surrogate Endpoint Evidence of Efficacy?". Milwaukee Journal Sentinel/MedPage Today.
- 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 (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): 2101–2108. PMID 18514303. doi:10.1016/S0140-6736(08)60661-3.
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- "Pfizer’s Phase III Trial in mRCC Turns Up Positive Results". 19 Nov 2010.
- "ODAC Unanimously Supports Axitinib for Renal Cell Carcinoma". 7 Dec 2011.
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- Tea Pemovska,Eric Johnson,Mika Kontro,Gretchen A. Repasky,Jeffrey Chen,Peter Wells,Ciarán N. Cronin,Michele McTigue,Olli Kallioniemi,Kimmo Porkka,Brion W. Murray & Krister Wennerberg. "Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation". Nature. doi:10.1038/nature14119.
- "FDA Prescribing Information" (PDF). 30 Jan 2012.
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- Zhang Y (Jan 2014). "Screening of kinase inhibitors targeting BRAF for regulating autophagy based on kinase pathways.". J Mol Med Rep 9 (1): 83–90. PMID 24213221. doi:10.3892/mmr.2013.1781.