Abstract C123: A phase 1 study to evaluate the absorption, metabolism, and excretion of the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) tivozanib.
Authors: Cotreau Monette M. , Hale Christine , Jacobson Lindsey , Oelke Claudine S. , Strahs Andrew L. , Kochan Robert , Slichenmyer William , Vargo Dennis 
Published: June 2012

Background: Tivozanib is a potent, selective, long half-life tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3. Tivozanib has demonstrated antitumor activity in a Phase II study in subjects with renal cell carcinoma. This study was conducted to determine the absorption, metabolism, and excretion of a single 1.5 mg dose of [14C]-tivozanib administered to healthy male subjects.

Methods: This study was approved by an independent institutional review board and enrolled 8 healthy male subjects; each received a single 1.5 mg (∼160 μCi) dose of oral [14C]-tivozanib. Whole blood, serum, urine, and feces were collected for up to 28 days post dose for assessment of total radioactivity and/or for determination of [14C]-tivozanib concentrations. All subjects were kept confined as inpatients for the duration of the study. Safety assessments included laboratory tests, electrocardiograms, physical examinations, vital signs, and recording of adverse events. Pharmacokinetic data were analyzed by noncompartmental methods.

Results: Subjects had a mean age of 32 years (range 19 to 46 years) and mean body mass index of 25 kg/m2 (range: 23 to 29 kg/m2). Of the 8 subjects enrolled, 7 completed the study. [14C]-tivozanib and total radioactivity were slowly absorbed and eliminated from serum; median Tmax was 10.0 hours, and mean (±SD) t1/2 for [14C]-tivozanib and total radioactivity in serum was 89.3 hours (± 23.5 hours) and 99.1 hours (± 32.5 hours), respectively. Mean (±SD) Cmax and AUC0−∞ values for [14C]-tivozanib were 12.1 ng/mL (±46.9 ng/mL) and 1084 ng*hr/mL (±417 ng*hr/mL), respectively; these values were approximately 93% and 80% of the values for total radioactivity in serum, respectively. Mean blood to serum concentration ratios ranged from 0.495 to 0.615 through 312 hours post dose, indicating minimal association of radioactivity with red blood cells. Overall, mean (±SD) recovery of total radioactivity was 91.1% (±11.0%), with 11.8% (±4.6%) recovered in urine and 79.3% (±8.8%) recovered in feces. No unchanged tivozanib was found in the urine. A single therapeutic dose of tivozanib was well tolerated in healthy subjects.

Conclusion: These results indicate that after an oral dose of 1.5 mg (∼160 μCi) of [14C]-tivozanib, the majority of circulating drug in the systemic circulation was unchanged tivozanib. The main route of elimination of [14C]-tivozanib was via feces, with at least 11.8% of the administered total radioactive dose being absorbed into systemic circulation. No unchanged tivozanib was found in the urine, indicating that tivozanib does not undergo renal excretion. In this study, the mean half-life of [14C]- tivozanib was 89.3 hours, one of the longest half-lives among VEGF TKIs. Tivozanib is currently being tested in a Phase III study in subjects with RCC and Phase I/II studies in other solid tumors.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C123.