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| Clinical data | |
|---|---|
| Trade names | Fotivda |
| Other names | AV-951 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a621018 |
| License data | |
| Routes of administration | By mouth |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Protein binding | >99% |
| Eliminationhalf-life | 4.5–5.1 days |
| Excretion | 79%feces, 12% urine |
| Identifiers | |
| CAS Number | |
| PubChemCID | |
| IUPHAR/BPS | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEBI | |
| ChEMBL | |
| CompTox Dashboard(EPA) | |
| Chemical and physical data | |
| Formula | C22H19ClN4O5 |
| Molar mass | 454.87 g·mol−1 |
| 3D model (JSmol) | |
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Tivozanib, sold under the brand nameFotivda, is a medication used for the treatment of advancedrenal cell carcinoma (kidney cancer).[3] It is an oralVEGF receptortyrosine kinase inhibitor.[3]
The most common side effects includefatigue (tiredness),hypertension (high blood pressure),diarrhea,decreased appetite,nausea,dysphonia (voice changes),hypothyroidism, cough, andstomatitis.[4][3][5]
Tivozanib was approved for medical use in the European Union in August 2017,[4] and in the United States in March 2021.[3][5]
In the United States, tivozanib isindicated for the treatment of adults with relapsed or refractory advanced renal cell carcinoma following two or more prior systemic therapies.[3]
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.[4]
Tivozanib must not be combined withSt. John's Wort, an inducer of the liver enzymeCYP3A4. It should not be taken during pregnancy as it isteratogenic, embryotoxic and fetotoxic in rats.[6]
The most common side effects in studies werehypertension (high blood pressure, in 48% of patients),dysphonia (hoarse voice, 27%),fatigue anddiarrhea (both 26%). Ahypertensive crisis occurred in 1% of patients.[6]
Administration of a single dose of tivozanib withrifampicin, a strong inducer of the enzyme CYP3A4, cuts thebiological 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 withketoconazole, a strong CYP3A4 inhibitor, has no relevant effects. The clinical significance of these findings is not known.[6]
Aquinolineurea derivative, tivozanib suppressesangiogenesis by being selectively inhibitory againstvascular endothelial growth factor (VEGF).[7] It is designed to inhibit all three VEGF receptors.[8]
After tivozanib is taken by mouth, highestblood 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 toplasma proteins, predominantlyalbumin. Although the enzymes CYP3A4 andCYP1A1 and severalUGTs are capable of metabolising the drug, over 90% circulate in unchanged form. The metabolites aredemethylation,hydroxylation andN-oxidation products andglucuronides.[6]
The biological half-life is 4.5 to 5.1 days; 79% being excreted via thefeces, mostly unchanged, and 12% via the urine, completely unchanged.[6]
Tivozanib is used in form of thehydrochloridemonohydrate, which is a white to light brown powder. It is practically insoluble in water and has low solubility inaqueous acids,ethanol andmethanol. It is nothygroscopic and notoptically active.[9]
It was discovered atKyowa Kirin and developed by Aveo Pharmaceuticals.[10][non-primary source needed]
The USFood and Drug Administration (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.[5] The trial compared participants who were randomly assigned to receive either tivozanib or sorafenib.[5] Both the participants and the health care providers knew which treatment was being given.[5] The treatment continued until the disease progression or the side effects became too toxic.[5] The trial compared the length of time participants were alive without progression between the two groups.[5] The trial was conducted at 120 of sites in 12 of countries in North America and Europe.[5] 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.[5]
Phase III results on advanced renal cell carcinoma suggested a 30% or 3 months improvement in medianprogression-free survival compared tosorafenib but showed an inferior overall survival rate of the experimental arm versus the control arm.[8][11] TheFood and Drug Administration'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 usedsorafenib to transition to tivozanib following progression disease but not those on the experimental arm using tivozanib to transition tosorafenib. Theapplication was formally rejected by the FDA in June 2013, saying that approval would require additional clinical studies.[11]
In 2016, Aveo Oncology announced the start of a second Phase III clinical study in third line advanced RCC patients.[12][non-primary source needed]
In August 2017, the European Commission approved tivozanib for medical use in the European Union.[4][13]
This article incorporates text from this source, which is in thepublic domain. This article incorporates text from this source, which is in thepublic domain.
