VEGFR1/FLT1 (IC50 = 0.1 nM); VEGFR2/Flk1 (IC50 = 0.18 nM); VEGFR2/KDR (IC50 = 0.2 nM); VEGFR3 (IC50 = 0.1 nM-0.3 nM nM); PDGFRβ (IC50 = 1.6 nM)

Axitinib may inhibit VEGF-mediated endothelial cell viability, tube formation, and downstream signaling in addition to cellular autophosphorylation of VEGFR. Variable cell lines with IC50 values of >10,000 nM (IGR-N91), 849 nM (IGR-NB8), 274 nM (SH-SY5Y), and 573 nM (non-VEGF stimulated HUVEC) are all inhibited by axitinib.[2]

Axitinib shows primary inhibition against orthotopically transplanted models of colon cancer (HCT-116), melanoma (M24met), and renal cell carcinoma (SN12C).[1] In IGR-N91 fenografts, axitinib reduces the Mean Vessels Density (MVD) to 21 from 49 in controls and delays the tumor growth by 11.4 days when compared to the controls (p.o. 30 mg/kg).[2] In the BT474 breast cancer model, axitinib at doses of 10-100 mg/kg dramatically suppresses growth and alters the tumor microvasculature.[3] In a variety of tumor types, such as melanoma, thyroid cancer, non-small cell lung cancer, and renal cell carcinoma, axitinib has demonstrated single-agent activity.

Generated are porcine aorta endothelial (PAE) cells that overexpress full-length VEGFR2, PDGFRβ, Kit, and NIH-3T3 cells that overexpress murine VEGFR2 (Flk-1) or PDGFRα. To prepare ELISA capture plates, 100 μL/well of 2.5 μg/mL anti-VEGFR2 antibody, 0.75 μg/mL anti-PDGFRβ antibody, 0.25 μg/mL anti-PDGFRα antibody, 0.5 μg/mL anti-KIT antibody, or 1.20 μg/mL anti-Flk-1 antibody are coated on the 96-well plates. Next, an ELISA is used to measure RTK phosphorylation.

A 96-well plate is seeded with 5 × 10⁴ cells, and the cells are cultured for a full day. Concentrations of axitinib ranging from 1 nM to 10 μM are added to the cells. MTS tetrazolium substrate is used to measure cell viability after 72 hours, and IC50 values are computed.

Mice and Rats: Mice bearing 400–600 mm³ M24met xenograft tumors receive either a single Axitinib dose or 0.5% carboxymethylcellulose/H₂O as a control. Samples of blood and tumor tissue are obtained for VEGFR-2 and pharmacokinetic analyses. The Bradford colorimetric assay is used to measure the total protein concentrations in tumor tissues.
Axitinib (30 mg/kg) is injected intraperitoneally twice into six-day-old Sprague-Dawley rats. Retinal tissue is extracted and lysed, animals are sacrificed, and immunoprecipitation and immunoblotting experiments are carried out. The Alpha Imager 8800 is used for densitometry analysis, and ECL-Plus is used for detection.

Absorption, Distribution and Excretion
After one 5 mg dose of axitinib, it takes about 2.5 to 4.1 hours to reach maximum plasma concentration.
Axitinib is mainly eliminated unchanged in the feces (41%) with 12% of the original dose as unchanged axitinib. There is also 23% eliminated in the urine, most of which are metabolites.
The volume of distribution is 160 L.
The average clearance of axitinib is 38 L/h.

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Metabolism / Metabolites
Axitinib undergoes mainly hepatic metabolism. CYP3A4 and CYP3A5 are the main hepatic enzymes while CYP1A2, CYP2C19, and UGT1A1 enzymes are secondary.

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Biological Half-Life
Axitinib has a half life of 2.5 to 6.1 hours.

Hepatotoxicity
In large clinical trials of axitinib, elevations in serum aminotransferase levels were common, occurring in up to 25% of patients. Values greater than 5 times the upper limit of normal (ULN), however, were uncommon, occurring in 1% to 2% of recipients. Furthermore, no instances of clinically apparent liver injury from axitinib were reported in prelicensure studies or during the more wide scale use since its approval. Nevertheless, periodic monitoring of liver tests during axitinib therapy is recommended.
Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of axitinib during breastfeeding. Because axitinib is more than 99% bound to plasma proteins, the amount in milk is likely to be low. The manufacturer recommends that breastfeeding be discontinued during axitinib therapy and for 2 weeks after the final dose of therapy. When axitinib is used in combination with avelumab or pembrolizumab, refer to those LactMed records.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Plasma protein binding for axitinib is high at over 99% with most protein binding to albumin followed by α1-acid glycoprotein.

[1]. The addition of AG-013736 to rractionated radiation improves tumor response without functionally normalizing the tumor vasculature. Cancer Res. 2007 Oct 15;67(20):9921-8.

[2]. Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res. 2008 Nov 15;14(22):7272-83.

[3]. Metabolic Symbiosis Enables Adaptive Resistance to Anti-angiogenic Therapy that Is Dependent on mTOR Signaling. Cell Rep. 2016 May 10;15(6):1144-60.

Axitinib is an indazole substituted at position 3 by a 2-(pyridin-2-yl)vinyl group and at position 6 by a 2-(N-methylaminocarboxy)phenylsulfanyl group. Used for the treatment of advanced renal cell carcinoma after failure of a first line systemic treatment. It has a role as an antineoplastic agent, a tyrosine kinase inhibitor and a vascular endothelial growth factor receptor antagonist. It is a member of indazoles, a member of pyridines, an aryl sulfide and a member of benzamides.
Axitinib is a second generation tyrosine kinase inhibitor that works by selectively inhibiting vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, VEGFR-3). Through this mechanism of action, axitinib blocks angiogenesis, tumour growth and metastases. It is reported to exhibit potency that is 50-450 times higher than that of the first generation VEGFR inhibitors. Axitinib is an indazole derivative. It is most commonly marketed under the name Inlyta® and is available in oral formulations.
Axitinib is a Kinase Inhibitor. The mechanism of action of axitinib is as a Receptor Tyrosine Kinase Inhibitor.
Axitinib is an oral tyrosine kinase inhibitor selective for vascular endothelial growth factor (VEGF) receptors -1, -2 and -3 that is used in the therapy of advanced renal cell carcinoma. Axitinib therapy is commonly associated with transient elevations in serum aminotransferase that are generally mild and asymptomatic. Axitinib has yet to be linked to instances of clinically apparent acute liver injury.
Axitinib is an orally bioavailable tyrosine kinase inhibitor. Axitinib inhibits the proangiogenic cytokines vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptor (PDGF), thereby exerting an anti-angiogenic effect.
A benzamide and indazole derivative that acts as a TYROSINE KINASE inhibitor of the VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR. It is used in the treatment of advanced RENAL CELL CARCINOMA.

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Drug Indication
Used in kidney cell cancer and investigated for use/treatment in pancreatic and thyroid cancer.
FDA Label
Inlyta is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of prior treatment with sunitinib or a cytokine.

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Mechanism of Action
Axitinib selectively blocks the tyrosine kinase receptors VEGFR-1 (vascular endothelial growth factor receptor), VEGFR-2, and VEGFR-3.

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Pharmacodynamics
Axitinib prevents the progression of cancer by inhibiting angiogenesis and blocking tumor growth.

C22H18N4OS

386.47

386.12

C, 68.37; H, 4.69; N, 14.50; O, 4.14; S, 8.30

319460-85-0

Axitinib-13C,d3;1261432-00-1;Axitinib-d3;1126623-89-9

6450551

white to off-white solid powder

1.4±0.1 g/cm3

668.9±55.0 °C at 760 mmHg

213-215ºC

358.3±31.5 °C

0.0±2.0 mmHg at 25°C

1.728

4.15

2

4

5

28

557

0

O=C(C1=C(SC2=CC3=C(C(/C=C/C4=CC=CC=N4)=NN3)C=C2)C=CC=C1)NC

RITAVMQDGBJQJZ-FMIVXFBMSA-N

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+

N-methyl-2-[[3-[(E)-2-pyridin-2-ylethenyl]-1H-indazol-6-yl]sulfanyl]benzamide

AG 013736; AG013736; Axitinib; AG 013736; Brand name: Inlyta

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.08 mg/mL (5.38 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.08 mg/mL (5.38 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (5.38 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly..

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Solubility in Formulation 4: 0.5% CMC: 30mg/mL

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Solubility in Formulation 5: 8.33 mg/mL (21.55 mM) in 20% HP-β-CD/10 mM citrate pH 2.0 (add these co-solvents sequentially from left to right, and one by one), clear solution; Need ultrasonic and adjust pH to 3 with H2O.

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 (Please use freshly prepared in vivo formulations for optimal results.)