Tivozanib, sold under the brand name Fotivda, is a medication used for the treatment of advanced

renal cell carcinoma Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the Proximal tubule, 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 cance ...

(kidney cancer). It is an oral VEGF receptor

tyrosine kinase A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...

inhibitor. The most common side effects include fatigue (tiredness), hypertension (high blood pressure),

diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...

decreased appetite Anorexia is a medical term for a loss of appetite. While the term in non-scientific publications is often used interchangeably with anorexia nervosa, many possible causes exist for a loss of appetite, some of which may be harmless, while others ...

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

dysphonia A hoarse voice, also known as dysphonia or hoarseness, is when the voice involuntarily sounds breathy, raspy, or strained, or is softer in volume or lower in pitch. A hoarse voice, can be associated with a feeling of unease or scratchiness in the ...

(voice changes), hypothyroidism, cough, and

stomatitis Stomatitis is inflammation of the mouth and lips. It refers to any inflammatory process affecting the mucous membranes of the mouth and lips, with or without oral ulceration. In its widest meaning, stomatitis can have a multitude of different cau ...

. Tivozanib was approved for medical use in the European Union in August 2017, Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. and in the United States in March 2021.

Medical uses

In the United States, tivozanib is

indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...

for the treatment of adults with relapsed or refractory advanced renal cell carcinoma following two or more prior systemic therapies. In the European Union, it is indicated for the treatment of adults with advanced renal cell carcinoma; and for the first line treatment of adults with advanced renal cell carcinoma and for adults who are VEGFR and mTOR pathway inhibitor-naïve following disease progression after one prior treatment with cytokine therapy for advanced renal cell carcinoma.

Contraindications

Tivozanib must not be combined with

St. John's Wort ''Hypericum perforatum'', known as St. John's wort, is a flowering plant in the family Hypericaceae and the type species of the genus ''Hypericum''. Possibly a hybrid between ''Hypericum maculatum, H. maculatum'' and ''Hypericum attenuatum, H. ...

, an inducer of the liver enzyme CYP3A4. It should not be taken during pregnancy as it is

teratogenic Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology. The related t ...

, embryotoxic and fetotoxic in rats.

Adverse effects

The most common side effects in studies were hypertension (high blood pressure, in 48% of patients),

(hoarse voice, 27%), fatigue and

(both 26%). A

hypertensive crisis Severely elevated blood pressure (equal to or greater than a systolic 180 or diastolic of 120—sometimes termed malignant or accelerated hypertension) is referred to as a hypertensive crisis, as blood pressure at this level confers a high risk ...

occurred in 1% of patients.

Interactions

Administration of a single dose of tivozanib with rifampicin, a strong inducer of the enzyme CYP3A4, cuts the

biological half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...

and total exposure (

area under the curve In mathematics, an integral assigns numbers to functions in a way that describes displacement, area, volume, and other concepts that arise by combining infinitesimal data. The process of finding integrals is called integration. Along with ...

) of tivozanib in half, but has no relevant influence on highest concentrations in the blood. Combination with ketoconazole, a strong CYP3A4 inhibitor, has no relevant effects. The clinical significance of these findings is not known.

Pharmacology

Mechanism of action

quinoline Quinoline is a heterocyclic aromatic organic compound with the chemical formula C9H7N. It is a colorless hygroscopic liquid with a strong odor. Aged samples, especially if exposed to light, become yellow and later brown. Quinoline is only sli ...

urea Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important ...

derivative, tivozanib suppresses angiogenesis by being selectively inhibitory against

vascular endothelial growth factor Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...

(VEGF). It is designed to inhibit all three VEGF receptors.

Pharmacokinetics

After tivozanib is taken by mouth, highest blood serum levels are reached after 2 to 24 hours. The total area under the curve is independent of food intake. When in the bloodstream, over 99% of the substance are bound to

plasma protein Blood-proteins, also termed plasma proteins, are proteins present in blood plasma. They serve many different functions, including transport of lipids, hormones, vitamins and minerals in activity and functioning of the immune system. Other blood pr ...

s, predominantly

albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...

. Although the enzymes CYP3A4 and CYP1A1 and several UGTs are capable of metabolising the drug, over 90% circulate in unchanged form. The metabolites are

demethylation Demethylation is the chemical process resulting in the removal of a methyl group (CH3) from a molecule. A common way of demethylation is the replacement of a methyl group by a hydrogen atom, resulting in a net loss of one carbon and two hydrogen at ...

, hydroxylation and N-oxidation products and

glucuronide A glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond. The glucuronides belong to the glycosides. Glucuronidation, the conversion of chemical compounds to glucu ...

s. The biological half-life is 4.5 to 5.1 days; 79% being excreted via the feces, mostly unchanged, and 12% via the urine, completely unchanged.

Chemistry

Tivozanib is used in form of the

hydrochloride In chemistry, a hydrochloride is an acid salt resulting, or regarded as resulting, from the reaction of hydrochloric acid with an organic base (e.g. an amine). An alternative name is chlorhydrate, which comes from French. An archaic alternative n ...

monohydrate, which is a white to light brown powder. It is practically insoluble in water and has low solubility in

aqueous An aqueous solution is a solution in which the solvent is water. It is mostly shown in chemical equations by appending (aq) to the relevant chemical formula. For example, a solution of table salt, or sodium chloride (NaCl), in water would be re ...

acids,

ethanol Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an alcohol with the chemical formula . Its formula can be also written as or (an ethyl group linked to a ...

and methanol. It is not

hygroscopic Hygroscopy is the phenomenon of attracting and holding water molecules via either absorption or adsorption from the surrounding environment, which is usually at normal or room temperature. If water molecules become suspended among the substan ...

and not optically active.

History

It was discovered at

Kyowa Kirin is a Japanese pharmaceutical and biotechnology company under the Kirin Holdings, and is among the 40 largest in the world by revenue. The company is headquartered in Chiyoda-ku, Tokyo and is a member of the Nikkei 225 stock index. History On ...

and developed by Aveo Pharmaceuticals. The US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) approved tivozanib based on evidence from one clinical trial of 350 adult participants with advanced kidney cancer (renal cell carcinoma) that had been treated with two or more prior medicines and has come back or did not respond to treatment. The trial compared participants who were randomly assigned to receive either tivozanib or sorafenib. Both the participants and the health care providers knew which treatment was being given. The treatment continued until the disease progression or the side effects became too toxic. The trial compared the length of time participants were alive without progression between the two groups. The trial was conducted at 120 of sites in 12 of countries in North America and Europe. The number of participants representing efficacy findings may differ from the number of patients representing safety findings due to different pools of study participants analyzed for efficacy and safety.

Clinical trials

Phase III results on advanced renal cell carcinoma suggested a 30% or 3 months improvement in median

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 ...

compared to sorafenib but showed an inferior overall survival rate of the experimental arm versus the control arm. The

's Oncologic Drugs Advisory Committee voted in May 2013 13 to 1 against recommending approval of tivozanib for renal cell carcinoma. The committee felt the drug failed to show a favorable risk-benefit ratio and questioned the equipose of the trial design, which allowed control arm patients who used sorafenib to transition to tivozanib following progression disease but not those on the experimental arm using tivozanib to transition to sorafenib. The application was formally rejected by the FDA in June 2013, saying that approval would require additional clinical studies. In 2016, Aveo Oncology announced the start of a second Phase III clinical study in third line advanced RCC patients.

Society and culture

Legal status

In August 2017, the European Commission approved tivozanib for medical use in the European Union.

References

External links

* {{Portal bar , Medicine Angiogenesis inhibitors Cancer treatments Isoxazoles Phenol ethers Quinolines Receptor tyrosine kinase inhibitors Ureas