Effects of ketoconazole or rifampin on the pharmacokinetics of tivozanib hydrochloride, a vascular endothelial growth factor receptor tyrosine kinase inhibitor.

The vascular endothelial growth factor (VEGF) pathway is associated with the promotion of endothelial cell proliferation, migration, and survival necessary for angiogenesis. VEGF and its three receptor isoforms are often overexpressed in many human solid tumors. Tivozanib is a potent, selective inhibitor of VEGF receptors 1, 2, and 3, with a long half-life. The purpose of these studies was to evaluate the effect of ketoconazole, a potent inhibitor of CYP3A4, and rifampin, a potent inducer of CYP3A4, on the pharmacokinetics of tivozanib. Two phase I, open-label, 2-period, single-sequence studies evaluated the effect of steady-state ketoconazole (NCT01363778) or rifampin (NCT01363804) on the pharmacokinetic profile, safety, and tolerability of a single oral 1.5-mg dose of tivozanib. Tivozanib was well tolerated in both studies. Steady-state ketoconazole did not cause a clinically significant change in the pharmacokinetics of a single dose of tivozanib; therefore, dosing of tivozanib with a CYP3A4 pathway inhibitor should not cause a clinically significant change in serum tivozanib levels. However, coadministration of tivozanib with rifampin caused a significant decrease in the area under the curve from 0 to infinity and half-life and an increase in clearance of tivozanib, which suggest increased clearance via the enhanced CYP3A4-mediated metabolism of tivozanib.

The effect of food on the pharmacokinetics of tivozanib hydrochloride.

Tivozanib hydrochloride (tivozanib) is a potent, selective tyrosine kinase inhibitor of the vascular endothelial growth factor receptors 1, 2, and 3, with a long half-life. This Phase I study evaluated the effect of food on tivozanib pharmacokinetics (PK). A single oral dose of tivozanib was administered to healthy subjects in a fasted/fed and a fed/fasted state. Thirty subjects enrolled; 29 completed the study. Maximum concentration (Cmax ) in the fed state was lower than in the fasted state (geometric means, 14.1 and 18.1 ng/mL). The geometric mean ratio (90% confidence interval) (fed/fasted states) for Cmax was 77.5% (72.9-82.4%), indicating a food effect on Cmax . There was no difference in tivozanib area under the curve to infinity (AUC0-∞ ) between states (geometric means, 2,377 and 2,198 ng h/mL). Geometric mean ratios also indicated no food effect on tivozanib AUC0-∞ . Other PK parameters were similar between states. The most commonly reported adverse events affected the gastrointestinal system and were mild in intensity. There were no clinically significant changes in other safety measures. In conclusion, food does not have an impact on the AUC0-∞ of tivozanib but does decrease Cmax approximately 23%, suggesting that this agent can be dosed with or without food.

Absorption, Metabolism, and Excretion of [(14) C]-Tivozanib, a Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Healthy Male Participants: A Phase I, Open-Label, Mass-Balance Study.

OBJECTIVE: To evaluate the absorption, metabolism, and excretion of tivozanib, a new investigational drug for renal cell carcinoma and solid malignancies. METHODS: Eight healthy male participants received a single 1.5-mg (˜160 µCi) dose of oral [(14) C]-tivozanib. Whole blood, serum, urine, and feces were evaluated up to 28 days postdose for pharmacokinetics, radioanalysis, and metabolites. Adverse events were recorded throughout the study. RESULTS: [(14) C]-tivozanib concentration peaked at 10.9 ± 5.84 hours. The mean serum half-life for [(14) C]-tivozanib was 89.3 ± 23.5 hours. The maximum concentration and area under the curve for [(14) C]-tivozanib were 12.1 ± 5.67 ng/mL and 1084 ± 417.0 ng·h/mL, respectively. Mean recovery of total radioactivity was 91.0% ± 11.0%; 79.3% ± 8.82% of the radioactivity was recovered in feces both as unchanged tivozanib and metabolites. In the urine, 11.8% ± 4.59% was recovered only as metabolites. No unchanged tivozanib was found in the urine. CONCLUSION: Tivozanib had a long half-life with no major circulating metabolite, was well tolerated as a single dose, and was primarily eliminated via feces with no unchanged tivozanib found in urine. These pharmacokinetic data of [(14) C]-tivozanib are consistent with previous studies of unlabeled tivozanib.

Antitumor activity and safety of tivozanib (AV-951) in a phase II randomized discontinuation trial in patients with renal cell carcinoma.

PURPOSE: The antitumor activity and safety of tivozanib, which is a potent and selective vascular endothelial growth factor receptor-1, -2, and -3 inhibitor, was assessed in patients with advanced/metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS: In this phase II, randomized discontinuation trial, 272 patients received open-label tivozanib 1.5 mg/d (one cycle equaled three treatment weeks followed by a 1-week break) orally for 16 weeks. Thereafter, 78 patients who demonstrated ≥ 25% tumor shrinkage continued to take tivozanib, and 118 patients with less than 25% tumor change were randomly assigned to receive tivozanib or a placebo in a double-blind manner; patients with ≥ 25% tumor growth were discontinued. Primary end points included safety, the objective response rate (ORR) at 16 weeks, and the percentage of randomly assigned patients who remained progression free after 12 weeks of double-blind treatment; secondary end points included progression-free survival (PFS). RESULTS: Of 272 patients enrolled onto the study, 83% of patients had clear-cell histology, 73% of patients had undergone nephrectomy, and 54% of patients were treatment naive. The ORR after 16 weeks of tivozanib treatment was 18% (95% CI, 14% to 23%). Of the 118 randomized patients, significantly more patients who were randomly assigned to receive double-blind tivozanib remained progression free after 12 weeks versus patients who received the placebo (49% v 21%; P = .001). Throughout the study, the ORR was 24% (95% CI, 19% to 30%), and the median PFS was 11.7 months (95% CI, 8.3 to 14.3 months) in the overall study population. The most common grade 3 and 4 treatment-related adverse event was hypertension (12%). CONCLUSION: Tivozanib was active and well tolerated in patients with advanced RCC. These data support additional development of tivozanib in advanced RCC.