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.
The osteogenic potential of AAV5hBMP6 was compared with that of ADhBMP6 in immunodeficient and immunocompetent rats. AAV5hBMP6 (2.3 x 10(12) particles) and ADhBMP6 (5 x 10(7) PFU) elicited viral antibody production in immunocompetent rats. Among rats that received AAV5hBMP6, the earliest time points at which the bone was visible under CT scanner were 30 days in 2-month-old Sprague-Dawley (SD) rats and 60 days in 18-month-old SD rats. The mean volumes of ectopic bone 90 days after viral injection were 0.31 +/- 0.14 cm(3) in athymic nude rats, 0.64 +/- 0.12 cm(3) in 2-month-old SD rats, and 0.21 +/- 0.10 cm(3) in 18-month-old SD rats. In contrast, among rats that received ADhBMP6, the earliest time points to observe the bone formation by CT scan were 15 days in 2-month-old rats and no bone formation in 18-month-old SD rats. The mean volumes of ectopic bone were 4.17 +/- 0.05 cm(3) in athymic nude rats and 0.06 +/- 0.03 cm(3) in 2-month-old SD rats. Although both types of viruses induced an immune response in immunocompetent animals, this response played different roles in the process of bone formation induced by the BMP6 vectors.
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.
Background: Tivozanib is a potent, selective, long half-life tyrosine kinase inhibitor of vascular endothelial growth factor receptors-1, -2, and -3 that is currently being tested in a Phase III study in patients with renal cell carcinoma and Phase I/II studies of other solid tumors. Previous preclinical and clinical studies have shown that tivozanib displays strong antiangiogenic and antitumor effects. Preclinical and retrospective electrocardiogram (ECG) analyses did not suggest an effect of tivozanib on QTc, although this has not been prospectively assessed according to ICH E14 Cardiac Assessment of New Drugs Guidelines. This open-label, non-randomized, single-arm study prospectively investigated the proarrhythmogenic potential of tivozanib on the QTcF interval and its morphology on the ECG and ECG-pharmacokinetic (PK) relationship in patients with advanced solid tumors. Methods: Patients with advanced solid tumors, an ECOG score ≤1 and life expectancy ≥3 months were eligible. Patients received 1.5 mg of tivozanib orally, once daily for 21 days. Patients with a repeated baseline QTcF >480 ms were excluded. Serial blood samples and time-matched, triplicate, 12-lead ECGs were collected on: Day 1 20–30 minutes pre-dose (no blood sample collected), immediately pre-dose, and at 2.5, 4, 5, 6, 8, and 10 hours post dose; Day 2 pre-dose evaluation was taken approximately 24 hours post Day 1 dose; Day 8 (±1 day) pre-dose, and at 2.5, 5, and 8 hours post dose; Day 21 pre-dose and at 2.5, 4, 5, 6, 8, and 10 hours post dose; and Day 22 at approximately 24 hours post Day 21 dose. Additional safety parameters were evaluated by assessment of clinical laboratory tests, physical examinations, vital signs, and recording of adverse events. Results: Fifty patients with advanced solid tumors (males, 17; median age, 63 years; 94% white) who received at least one dose of tivozanib were evaluable for the present study. Preliminary adverse event data showed that there were no clinically significant changes in QTcF from baseline. Further analysis will be completed, and final safety and ECG-PK modeling will be presented. Conclusions: Preliminary data suggest that tivozanib at 1.5 mg daily over a 21-day period does not cause clinically significant prolongation of QT/QTc over baseline. Data from this study suggest that the safety and PK profile of tivozanib was similar to that observed in previous studies, and that the findings are consistent with the ECG evaluation in a monkey telemetry study. 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 C121.
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