Axitinib

Absorption

After one 5 mg dose of axitinib, it takes about 2.5 to 4.1 hours to reach maximum plasma concentration.

Toxicity

Some of the more serious toxic effects seen in patients taking axitinib include, but are not limited to, hypertension, thrombotic events, hemorrhage, and GI perforation.

Description

Axitinib is a VEGFR inhibitor (IC50s = 1.2, 0.25, and 0.29 nM for VEGFR1, -2, and -3, respectively). It also inhibits c-Kit and PDGFRβ (IC50s = 1.7 and 1.6 nM, respectively). It inhibits VEGF-induced migration of and tube formation by human umbilical vein endothelial cells (HUVECs). In January 2012, the US FDA approved axitinib (also referred to as AG-013736) for the treatment of advanced renal cell carcinoma (RCC) for patients who have not responded to prior therapy.

Chemical properties

Off-White Solid

Characteristics

Class: receptor tyrosine kinase
Treatment: RCC
Oral bioavailability = 58%
Elimination half-life = 2.5–6.1 h
Protein binding = 99%

The Uses of Axitinib

Axitinib (AG-013736) is a multi-target inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFRβ and c-Kit with IC50 of 0.1 nM, 0.2 nM, 0.1-0.3 nM, 1.6 nM and 1.7 nM, respectively. 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. 

Indications

Used in kidney cell cancer and investigated for use/treatment in pancreatic and thyroid cancer.

Definition

ChEBI: 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 tr atment.

Biochem/physiol Actions

Axitinib (AG-013736) is an orally available, potent (picomolar) and selective tyrosine kinase inhibitor that blocks VEGF receptors 1, 2 and 3. The drug blocks VEGF-mediated endothelial cell survival, tube formation, and downstream signaling through endothelial nitric oxide synthase, Akt and extracellular signal-regulated kinase.

Pharmacokinetics

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

Clinical Use

Sold under the brand name Inlyta® by Pfizer, Inc., axitinib was approved by the FDA in January 2012 for the treatment of advanced renal cell carcinoma (RCC), specifically after the failure of other systemic treatments. Axitinib slows cancer cell proliferation by inhibition of the vascular endothelial growth factor (VEGF)/VEGF receptor tyrosine (RTK) signaling pathway. In particular, axitinib is a potent inhibitor of VEGF/RTK 1-3, which selectively slows angiogenesis, vascular permeability, and blood flow in solid tumors.

Side Effects

The side effects that you should report to your doctor include:
allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue;
high blood pressure;
seizures;
signs and symptoms of bleeding such as bloody or black, tarry stools; red or dark-brown urine; spitting up blood or brown material that looks like coffee grounds; red spots on the skin; unusual bruising or bleeding from the eye, gums, or nose;
signs and symptoms of a blood clot such as breathing problems; changes in vision; chest pain; severe, sudden headache; pain, swelling, warmth in the leg; trouble speaking; sudden numbness or weakness of the face, arm, or leg;
stomach pain.
The side effects that usually do not require medical attention include constipation cough, diarrhea, loss of appetite, nausea, and vomiting.

Synthesis

Numerous patents and papers have been disclosed on the synthesis of axitinib, a recently published manuscript details the development of the manufacturing route, and this route is depicted in the scheme. The synthesis began with Migita coupling of commercial iodide 17 with thiophenol 18. Interestingly, this transformation?ˉs efficiency relied upon attention to the number of equivalents of base and an inert atmosphere in the reaction vessel, conditions which minimized catalyst poisoning during the reaction. Without isolation, indazole 19 was iodinated to afford diarylthioether 20 in 85-90% yield over the two steps. Protection of the indazole within 20 as its acetamide preceeded a Heck reaction with 2-vinylpyridine, and then subsequent removal of the indazole protection followed by a series of recrystallizations yielded axitinib (IV) in a combined 62% yield over the final 4 steps.

Drug interactions

Potentially hazardous interactions with other drugs
Antipsychotics: avoid with clozapine (increased risk of agranulocytosis); avoid with pimozide.
Concomitant use with strong CYP3A4/5 inhibitors: avoid; however, if concomitant use cannot be avoided then reduce the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability; if CYP3A4/5 inhibitor is discontinued, then increase the axitinib dose used prior to initiation of the strong inhibitor after 3-5 half-lives of the inhibitor (strong CYP3A4/5 inhibitors include ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, ritonavir, saquinavir, and voriconazole).

Metabolism

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

References

1) Hu-Lowe?et al.?(2008),?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; Cancer Res.,?14?7272 2) Ma and Waxman (2008),?Modulation of the antitumor activity of metronomic cyclophosphamide by the angiogenesis inhibitor axitinib; Mol. Cancer Ther.,?7?79 3) Pemovska?et al.?(2015),?Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation; Nature,?519?102 4) Rixe?et al.?(2007),?Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer; a phase II study; Lancet Oncol.,?8?975 5) Yuan?et al.?(2014),?Axitinib augments antitumor activity in renal cell carcinoma via STAT3-dependent reversal of myeloid-derived suppressor cell accumulation;?Biomed.Pharmacother.?68?751 6) Zhang?et al.?(2014),?Axitinib, a selective inhibitor of vascular endothelial growth factor receptor, exerts an anticancer effect in melanoma through promoting antitumor immunity;?Anticancer Drugs?25?204