Axitinib

Axitinib

Systematic (IUPAC) name
N-Methyl-2-[[3-[(E)-2-pyridin-2-ylethenyl]-1H-indazol-6-yl]sulfanyl]benzamide
Clinical data
Trade names	Inlyta
AHFS/Drugs.com	monograph
MedlinePlus	a612017
License data	EU EMA: Inlyta US FDA: Axitinib
Pregnancy category	AU: D US: D (Evidence of risk)
Routes of administration	Oral
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	58%[1]
Protein binding	>99%[1]
Metabolism	Hepatic (mostly CYP3A4/CYP3A5-mediated but with some contributions from CYP1A2, CYP2C19, UGT1A1)[1]
Biological half-life	2.5-6.1 hours[1]
Excretion	Faeces (41%; 12% as unchanged drug), urine (23%)[1]
Identifiers
CAS Number	319460-85-0
ATC code	L01XE17 (WHO)
PubChem	CID 6450551
IUPHAR/BPS	5659
ChemSpider	4953153
UNII	C9LVQ0YUXG
KEGG	D03218
ChEBI	CHEBI:66910
ChEMBL	CHEMBL1289926
PDB ligand ID	AXI (PDBe, RCSB PDB)
Chemical data
Formula	C22H18N4OS
Molar mass	386.469 g/mol
SMILES O=C(NC)c4ccccc4Sc1ccc2c(c1)nnc2\C=C\c3ncccc3
InChI 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+ Key:RITAVMQDGBJQJZ-FMIVXFBMSA-N
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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] It was approved 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]

Medical uses

A Phase II clinical trial showed good response in combination chemotherapy with gemcitabine for advanced pancreatic cancer.^[7] 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.^[8]

In 2010, a Phase III trial for previously treated metastatic renal cell carcinoma (mRCC) showed significantly extended progression-free survival when compared to sorafenib.^[9] 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.^[10]

It has received FDA (27 January 2012), EMA (13 September 2012), MHRA (3 September 2012) and TGA (26 July 2012) approval for use as a treatment for renal cell carcinoma.^{[11][12][13][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.

Contraindications

The only contraindication to axitinib is hypersensitivity to axitinib.^[14]

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

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 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).^[17]

It was also proposed that it might act by inducing autophagy, as some other tyrosine kinase inhibitors, like sorafenib.^[18]

It has also been shown^[15] 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^[1]

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%)

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; 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. doi:10.1016/j.mri.2006.09.041. PMID 17371720.
3. Rini, B; Rixe, O; Bukowski, R; Michaelson, MD; Wilding, G; Hudes, G; Bolte, O; Steinfeldt, H; Reich, SD; Motzer, R (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.
4. Rugo, HS; Herbst, RS; Liu, G; Park, JW; Kies, MS; Steinfeldt, HM; Pithavala, YK; Reich, SD; Freddo, JL; Wilding, G (August 2005). "Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results" (PDF). 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. John Fauber, Elbert Chu (Oct 27, 2014). "The Slippery Slope: Is a Surrogate Endpoint Evidence of Efficacy?". Milwaukee Journal Sentinel/MedPage Today.
7. 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. doi:10.1016/S0140-6736(08)60661-3. PMID 18514303.
8. "Pfizer pancreatic cancer drug fails, trial halted". Reuters. January 30, 2009.
9. "Pfizer’s Phase III Trial in mRCC Turns Up Positive Results". 19 Nov 2010.
10. "ODAC Unanimously Supports Axitinib for Renal Cell Carcinoma". 7 Dec 2011.
11. "INLYTA (axitinib) tablet, film coated [Pfizer Laboratories Div Pfizer Inc]". DailyMed. Pfizer Laboratories Div Pfizer Inc. September 2013. Retrieved 25 January 2014.
12. "Inlyta : EPAR - Product Information" (PDF). European Medicines Agency. Pfizer Ltd. 17 December 2013. Retrieved 25 January 2014.
13. "Inlyta 1 mg 3mg, 5 mg & 7mg film-coated tablets - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Pfizer Limited. 5 December 2013. Retrieved 25 January 2014.
14. "PRODUCT INFORMATION INLYTA (axitinib)" (PDF). TGA eBusiness Services. Pfizer Australia Pty Ltd. 5 July 2013. Retrieved 25 January 2014.
15. 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 519: 102–105. doi:10.1038/nature14119.
16. "FDA Prescribing Information" (PDF). 30 Jan 2012.
17. Escudier, B; Gore, M. "Axitinib for the Management of Metastatic Renal Cell Carcinoma" (PDF). Drugs in R&d 11 (2): 113–126. doi:10.2165/11591240-000000000-00000. PMC 3585900. PMID 21679004.
18. 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. doi:10.3892/mmr.2013.1781. PMID 24213221.