Tivozanib

Tivozanib (trade name Fotivda) is an oral VEGF receptor tyrosine kinase inhibitor. It has completed a Phase 3 investigation for the treatment of first line (treatment naive) patients with renal cell carcinoma.[1] The results from this first line study did not lead to US FDA approval, but tivozanib was approved by the European Medicines Agency (EMA) in August 2017.[2]

Tivozanib
Clinical data
Trade namesFotivda
Other namesAV-951
AHFS/Drugs.comUK Drug Information
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • UK: POM (Prescription only)
Pharmacokinetic data
Protein binding>99%
Elimination half-life4.5–5.1 days
Excretion79% faeces, 12% urine
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC22H19ClN4O5
Molar mass454.87 g·mol−1
3D model (JSmol)

Contraindications

Tivozanib must not be combined with St. John's Wort, an inducer of the liver enzyme CYP3A4 (see interactions below). It should not be taken during pregnancy as it is teratogenic, embryotoxic and fetotoxic in rats.[3]

Adverse effects

The most common side effects in studies were hypertension (high blood pressure, in 48% of patients), dysphonia (hoarse voice, 27%), fatigue and diarrhoea (both 26%). A hypertensive crisis occurred in 1% of patients.[3]

Interactions

Administration of a single dose of tivozanib with rifampicin, a strong inducer of the enzyme CYP3A4, cuts the biological half-life and total exposure (AUC) 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.[3]

Pharmacology

Mechanism of action

A quinoline urea derivative, tivozanib suppresses angiogenesis by being selectively inhibitory against vascular endothelial growth factor.[4] It was developed by AVEO Pharmaceuticals.[5] It is designed to inhibit all three VEGF receptors.[6]

Pharmacokinetics

After tivozanib is taken by mouth, highest blood serum levels are reached after 2 to 24 hours. The total AUC is independent of food intake. When in the bloodstream, over 99% of the substance are bound to plasma proteins, predominantly albumin. 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, hydroxylation and N-oxidation products and glucuronides.[3]

The biological half-life is 4.5 to 5.1 days; 79% being excreted via the faeces, mostly unchanged, and 12% via the urine, completely unchanged.[3]

Chemistry

Tivozanib is used in form of the hydrochloride monohydrate, which is a white to light brown powder. It is practically insoluble in water and has low solubility in aqueous acids, ethanol and methanol. It is not hygroscopic and not optically active.[7]

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 but showed an inferior overall survival rate of the experimental arm versus the control arm.[6][8] The Food 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 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.[8]

In 2016 AVEO Oncology published data in conjunction with the ASCO meeting showing a geographical location effect on overall survival in the Phase III trial.[9]

In 2016 AVEO Oncology announced the start of a second Phase III clinical study in third line advanced RCC patients.[10]

In 2016 EUSA Pharma and AVEO Oncology announced that tivozanib had been submitted to the European Medicines Agency for review under the centralised procedure. [11]

In June 2017 the EMA Scientific Committee recommended tivozanib for approval in Europe, with approval expected in September.[12]

In August 2017 the European Commission (EC) formally approved tivozanib in Europe.[13]

References
  1. Tivozanib is currently being evaluated in the pivotal Phase 3 TIVO-3 trial, a randomized, controlled, multi-center, open-label study to compare tivozanib to sorafenib in subjects with refractory advanced RCC. FDA approval is expected in 2018. A Study of Tivozanib (AV-951), an Oral VEGF Receptor Tyrosine Kinase Inhibitor, in the Treatment of Renal Cell Carcinoma, clinicaltrials.gov
  2. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004131/human_med_002146.jsp&mid=WC0b01ac058001d124.
  3. "Fotivda: EPAR – Product Information" (PDF). European Medicines Agency. 2017-11-22.
  4. Campas, C., Bolos, J., Castaner, R (2009). "Tivozanib". Drugs Fut. 34 (10): 793.CS1 maint: multiple names: authors list (link)
  5. Aveo Kidney Cancer Drug Shows Success; Shares Up, By John Kell, Dow Jones Newswires
  6. "Phase III Results Lead Aveo and Astellas to Plan Regulatory Submissions for Tivozanib". 3 Jan 2012.
  7. "Fotivda: EPAR – Public assessment report" (PDF). European Medicines Agency. 2017-11-22.
  8. "FDA Rejects Renal Cancer Drug Tivozanib". MedPage Today. June 30, 2013.
  9. http://meetinglibrary.asco.org/content/165081-176
  10. http://investor.aveooncology.com/phoenix.zhtml?c=219651&p=irol-newsArticle&ID=2172669
  11. http://www.eusapharma.com/files/EUSA-Pharma-file-tivozanib-in-EU-March-2016.pdf
  12. "AVEO Pharma surges 48% on recommendation for European approval of its cancer drug". Market Watch. June 28, 2017. Retrieved June 28, 2017.
  13. "AVEO Oncology Announces Fotivda (tivozanib) Approved in the European Union for the Treatment of Advanced Renal Cell Carcinoma" (PDF). AVEO Oncology. August 28, 2017. Retrieved February 9, 2018.
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