|Metabolism||Hepatic (mostly CYP3A4/CYP3A5-mediated but with some contributions from CYP1A2, CYP2C19, UGT1A1)|
|Elimination half-life||2.5-6.1 hours|
|Excretion||Faeces (41%; 12% as unchanged drug), urine (23%)|
|Chemical and physical data|
|Molar mass||386.469 g/mol g·mol−1|
|3D model (JSmol)|
|(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.
Approvals and indications
Renal cell carcinoma
It has received approval for use as a treatment for renal cell carcinoma from US FDA (27 January 2012), EMA (13 September 2012), UK MHRA (3 September 2012) and Australian TGA (26 July 2012) .
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 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.
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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