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 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, resp ...

(kidney cancer). It is an oral

VEGF 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 ...

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 Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...

(tiredness),

hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...

(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 wi ...

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 i ...

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 (voice changes),

hypothyroidism Hypothyroidism (also called ''underactive thyroid'', ''low thyroid'' or ''hypothyreosis'') is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. It can cause a number of symptoms, such as po ...

, cough, and stomatitis. 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 '' H. maculatum'' and '' H. attenuatum'', the species can be found a ...

, an inducer of the liver enzyme

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 t ...

. 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

(high blood pressure, in 48% of patients), dysphonia (hoarse voice, 27%),

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 Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), mycobacterium avium complex, ''Mycobacterium avium'' complex, leprosy, and Legionnaires’ disease. ...

, a strong inducer of the enzyme CYP3A4, cuts the biological half-life and total exposure ( area under the curve) of tivozanib in half, but has no relevant influence on highest concentrations in the blood. Combination with

ketoconazole Ketoconazole, sold under the brand name Nizoral among others, is an antiandrogen and antifungal medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin infections such as tinea, cutaneous candid ...

, a strong CYP3A4 inhibitor, has no relevant effects. The clinical significance of these findings is not known.

Pharmacology

Mechanism of action

A quinoline

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 r ...

derivative, tivozanib suppresses

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 splitting ...

by being selectively inhibitory against vascular endothelial growth factor (VEGF). It is designed to inhibit all three VEGF receptors.

Pharmacokinetics

After tivozanib is taken by mouth, highest

blood serum Serum () is the fluid and solute component of blood which does not play a role in clotting. It may be defined as blood plasma without the clotting factors, or as blood with all cells and clotting factors removed. Serum includes all proteins not u ...

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 Cytochrome P450, family 1, subfamily A, polypeptide 1 is a protein that in humans is encoded by the ''CYP1A1'' gene. The protein is a member of the cytochrome P450 superfamily of enzymes. Function Metabolism of xenobiotics and drugs CYP1A1 ...

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

hydroxylation In chemistry, hydroxylation can refer to: *(i) most commonly, hydroxylation describes a chemical process that introduces a hydroxyl group () into an organic compound. *(ii) the ''degree of hydroxylation'' refers to the number of OH groups in a ...

and

N-oxidation In chemistry, an amine oxide, also known as an amine ''N''-oxide or simply ''N''-oxide, is a chemical compound that contains the functional group , a nitrogen-oxygen coordinate covalent bond with three additional hydrogen and/or substituent-grou ...

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 glucur ...

s. The biological half-life is 4.5 to 5.1 days; 79% being excreted via the

feces Feces ( or faeces), known colloquially and in slang as poo and poop, are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the large intestine. Feces contain a relati ...

, mostly unchanged, and 12% via the urine, completely unchanged.

Chemistry

Tivozanib is used in form of the hydrochloride

monohydrate In chemistry, a hydrate is a substance that contains water or its constituent elements. The chemical state of the water varies widely between different classes of hydrates, some of which were so labeled before their chemical structure was underst ...

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

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

and

methanol Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical and the simplest aliphatic alcohol, with the formula C H3 O H (a methyl group linked to a hydroxyl group, often abbreviated as MeOH). It is a ...

. 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 substance ...

and not

optically active Optical rotation, also known as polarization rotation or circular birefringence, is the rotation of the orientation of the plane of polarization about the optical axis of linearly polarized light as it travels through certain materials. Circul ...

History

It was discovered at Kyowa Kirin 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 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 r ...

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

to transition to tivozanib following progression disease but not those on the experimental arm using tivozanib to transition to

. The

application Application may refer to: Mathematics and computing * Application software, computer software designed to help the user to perform specific tasks ** Application layer, an abstraction layer that specifies protocols and interface methods used in a c ...

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