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.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. 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. History
It was discovered by Kyowa Kirin and developed by AVEO Pharmaceuticals. 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. The Food and Drug Administrations 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 published data in conjunction with the ASCO meeting showing a geographical location effect on overall survival in the Phase III trial.In 2016, AVEO Oncology announced the start of a second Phase III clinical study in third line advanced RCC patients.In 2016, EUSA Pharma and AVEO Oncology announced that tivozanib had been submitted to the European Medicines Agency for review under the centralised procedure.In June 2017, the EMA Scientific Committee recommended tivozanib for approval in Europe, with approval expected in September.In August 2017, the European Commission (EC) formally approved tivozanib in Europe. References
External links
"Tivozanib". Drug Information Portal. U.S. National Library of Medicine.