Abstract
The goal of this study was to evaluate the pharmacokinetics, mass balance, metabolism, routes and extent of elimination, and safety of a single oral dose of 14C-labeled brivanib alaninate and the safety and tolerability of brivanib after multiple doses in patients with advanced or metastatic solid tumors. This was a two-part, single-center, open-label, single oral-dose (part A) followed by multiple-dose (part B) study in patients with advanced or metastatic solid tumors. In part A, patients received a single dose of [14C]brivanib alaninate and in part B patients received 800 mg of nonradiolabeled brivanib alaninate every day. Four patients (two white, two black: two with non–small-cell lung cancer, one with ovarian cancer, and one with renal cell carcinoma) were treated in both parts. The median time to reach the maximal plasma concentration of brivanib was 1 h, geometric mean maximal plasma concentration was 6146 ng/ml, mean terminal half-life was 13.8 h, and geometric mean apparent oral clearance was 14.7 l/h. After a single oral dose of [14C]brivanib alaninate, 12.2 and 81.5% of administered radioactivity was recovered in urine and feces, respectively. Brivanib alaninate was completely converted to the active moiety, brivanib, and the predominant route of elimination was fecal. Renal excretion of unchanged brivanib was minimal. Brivanib was well tolerated; fatigue was the most frequent adverse event occurring in all patients and the most frequent treatment-related adverse event in three (75%). The best clinical response in one patient was stable disease; the other three had progressive disease. Brivanib alaninate was rapidly absorbed and extensively metabolized after a single 800-mg oral dose; the majority of drug-related radioactivity was excreted in feces.
Footnotes
This work was supported by the National Institutes of Health National Cancer Institute [Grant 5P30-CA043703] (to R.G.).
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.033951.
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ABBREVIATIONS:
- VEGF
- vascular endothelial growth factor
- FGF
- fibroblast growth factor
- HCC
- hepatocellular carcinoma
- TKI
- tyrosine kinase inhibitor
- PK
- pharmacokinetics
- BMS-540215
- (R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1f][1,2,4]triazin-6-yloxy)propan-2-ol
- HPLC
- high-performance liquid chromatography
- AE
- adverse event
- TRA
- total radioactivity
- Cmax
- maximum plasma concentration
- Tmax
- time to reach maximum observed plasma concentration
- AUC0-inf
- area under the concentration-time curve from time 0 extrapolated to infinity
- AUC0-T
- AUC from time 0 to the last quantifiable concentration
- t1/2
- terminal elimination half-life
- CLR
- renal clearance
- CL/F
- apparent total body clearance.
- Received April 22, 2010.
- Accepted July 29, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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