Axitinib, sold under the brand name Inlyta, is a small molecule

tyrosine kinase inhibitor A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosph ...

developed by

Pfizer Pfizer Inc. ( ) is an American multinational pharmaceutical and biotechnology corporation headquartered on 42nd Street in Manhattan, New York City. The company was established in 1849 in New York by two German entrepreneurs, Charles Pfize ...

. It has been shown to significantly inhibit growth of breast cancer in animal (

xenograft Xenotransplantation (''xenos-'' from the Greek meaning "foreign" or strange), or heterologous transplant, is the transplantation of living cells, tissues or organs from one species to another. Such cells, tissues or organs are called xenograf ...

) models and has shown partial responses in clinical trials with

renal cell carcinoma Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. RCC is the most common type of kidney cancer in adults, re ...

(RCC) and several other tumour types. It was approved to treat renal cell carcinoma by the U.S. Food and Drug Administration after showing a modest increase in

progression-free survival Progression-free survival (PFS) is "the length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse". In oncology, PFS usually refers to situations in which a tumor is p ...

, though there have been reports of fatal adverse effects.

Approvals and indications

Renal cell carcinoma

It has received approval for use as a treatment for renal cell carcinoma from the US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

(FDA) (27 January 2012), the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Eur ...

(EMA) (13 September 2012), the UK

Medicines and Healthcare products Regulatory Agency The Medicines and Healthcare products Regulatory Agency (MHRA) is an executive agency of the Department of Health and Social Care in the United Kingdom which is responsible for ensuring that medicines and medical devices work and are acceptab ...

(MHRA) (3 September 2012) and the Australian

Therapeutic Goods Administration The Therapeutic Goods Administration (TGA) is the medicine and therapeutic regulatory agency of the Australian Government. As part of the Department of Health and Aged Care, the TGA regulates the quality, supply and advertising of medicines, p ...

(TGA) (26 July 2012).

Clinical trials

A Phase II

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...

showed good response in combination chemotherapy with

gemcitabine Gemcitabine, with brand names including Gemzar, is a chemotherapy medication. It treats cancers including testicular cancer, breast cancer, ovarian cancer, non-small cell lung cancer, pancreatic cancer, and bladder cancer. It is administered by ...

for advanced

pancreatic cancer Pancreatic cancer arises when cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a mass. These cancerous cells have the ability to invade other parts of the body. A number of types of pancr ...

. However, Pfizer reported on January 30, 2009, that Phase III

s 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

(mRCC) showed significantly extended progression-free survival when compared to

sorafenib Sorafenib, sold under the brand name Nexavar, is a kinase inhibitor drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma), advanced primary liver cancer ( hepatocellular carcinoma), FLT3-ITD positive AML and ra ...

. In December 2011, the Oncologic Drugs Advisory Committee (ODAC) voted unanimously to recommend that

US FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...

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. It has also been studied in combination with the ALK1 inhibitor dalantercept. A study published in 2015 showed that axitinib effectively inhibits a mutated gene ( BCR-ABL1 315I that is common in

chronic myeloid leukemia Chronic myelogenous leukemia (CML), also known as chronic myeloid leukemia, is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of myeloid cells in the bone marrow and the accumulati ...

s and adult acute lymphoblastic leukemias which have become resistant to other

tyrosine kinase inhibitors A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a ph ...

imatinib Imatinib, sold under the brand names Gleevec and Glivec (both marketed worldwide by Novartis) among others, is an oral chemotherapy medication used to treat cancer. Imatinib is a small molecule inhibitor targeting multiple receptor tyrosine kin ...

. 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.

Adverse effects

Diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia,

hand-foot syndrome Chemotherapy-induced acral erythema, also known as palmar-plantar erythrodysesthesia or hand-foot syndrome is reddening, swelling, numbness and desquamation (skin sloughing or peeling) on palms of the hands and soles of the feet (and, occasionally ...

, weight decreased, vomiting, asthenia, and constipation are the most common side effects occurring in more than 20% of patients.

Interactions

Coadministration with strong

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules ( xenobiotics), such as toxins or drugs, so that they can be removed from ...

CYP3A5 Cytochrome P450 3A5 is a protein that in humans is encoded by the ''CYP3A5'' gene. Tissue distribution ''CYP3A5'' encodes a member of the cytochrome P450 superfamily of enzymes. Like most of the cytochrome P450, the CYP3A5 is expressed in the ...

inhibitors should be avoided where possible as they may reduce plasma clearance of axitinib.

Mechanism of action

Its primary mechanism of action is thought to be

vascular endothelial growth factor receptor VEGF receptors are receptors for vascular endothelial growth factor (VEGF). There are three main subtypes of VEGFR, numbered 1, 2 and 3. Also, they may be membrane-bound (mbVEGFR) or soluble (sVEGFR), depending on alternative splicing. Inh ...

1–3,

c-KIT Proto-oncogene c-KIT is the gene encoding the receptor tyrosine kinase protein known as tyrosine-protein kinase KIT, CD117 (cluster of differentiation 117) or mast/stem cell growth factor receptor (SCFR). Multiple transcript variants encoding dif ...

and

PDGFR Platelet-derived growth factor receptors (PDGF-R) are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor (PDGF) family. PDGF subunits -A and -B are important factors regulating cell proliferation, cellula ...

inhibition, this, in turn, enables it to inhibit

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splittin ...

(the formation of new blood vessels by tumours). It was also proposed that it might act by inducing

autophagy Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...

, as some other tyrosine kinase inhibitors, like

. It has also been shown to bind (in a different conformation from the VEGF binding) to the

BCR-ABL The Philadelphia chromosome or Philadelphia translocation (Ph) is a specific genetic abnormality in chromosome 22 of leukemia cancer cells (particularly chronic myeloid leukemia (CML) cells). This chromosome is defective and unusually short becaus ...

fusion protein, specifically inhibiting the drug-resistant T315I mutant isoform.

Pharmacokinetics

Society and culture

Brand names

Bangladesh Bangladesh (}, ), officially the People's Republic of Bangladesh, is a country in South Asia. It is the eighth-most populous country in the world, with a population exceeding 165 million people in an area of . Bangladesh is among the mo ...

it is under the trade name Axinix. In

Germany Germany,, officially the Federal Republic of Germany, is a country in Central Europe. It is the second most populous country in Europe after Russia, and the most populous member state of the European Union. Germany is situated betwee ...

Switzerland ). Swiss law does not designate a ''capital'' as such, but the federal parliament and government are installed in Bern, while other federal institutions, such as the federal courts, are in other cities (Bellinzona, Lausanne, Luzern, Neuchâtel ...

and other European countries it is available under the trade name Inlyta.

References

External links

* {{Portal bar , Medicine Receptor tyrosine kinase inhibitors 2-Pyridyl compounds Alkene derivatives Pfizer brands Indazoles Thioethers Benzamides