Abstract
This mass balance study investigated the metabolism and excretion of eribulin, a nontaxane microtubule dynamics inhibitor with a novel mechanism of action, in patients with advanced solid tumors. A single approximately 2 mg (approximately 80 μCi) dose of [14C]eribulin acetate was administered as a 2 to 5 min bolus injection to six patients on day 1. Blood, urine, and fecal samples were collected at specified time points on days 1 to 8 or until sample radioactivity was ≤1% of the administered dose. Mean plasma eribulin exposure (627 ng · h/ml) was comparable with that of total radioactivity (568 ng Eq · h/ml). Time-matched concentration ratios of eribulin to total radioactivity approached unity in blood and plasma, indicating that unchanged parent compound constituted almost all of the eribulin-derived radioactivity. Only minor metabolites were detected in plasma samples up to 60 min postdose, pooled across patients, each metabolite representing ≤0.6% of eribulin. Elimination half-lives for eribulin (45.6 h) and total radioactivity (42.3 h) were comparable. Eribulin-derived radioactivity excreted in feces was 81.5%, and that of unchanged eribulin was 61.9%. Renal clearance (0.301 l/h) was a minor component of total eribulin clearance (3.93 l/h). Eribulin-derived radioactivity excreted in urine (8.9%) was comparable with that of unchanged eribulin (8.1%), indicating minimal excretion of metabolite(s) in urine. Total recovery of the radioactive dose was 90.4% in urine and feces. Overall, no major metabolites of eribulin were detected in plasma. Eribulin is eliminated primarily unchanged in feces, whereas urine constitutes a minor route of elimination.
Footnotes
This work was supported by Eisai Inc.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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ABBREVIATIONS:
- MBC
- metastatic breast cancer
- ACN
- acetonitrile
- AE
- adverse event
- AUC
- area under the concentration-time curve
- CL
- clearance
- CLr
- renal clearance
- EoI
- end of the 2 to 5 min [14C]eribulin infusion
- FDA
- U.S. Food and Drug Administration
- HPLC
- high-performance liquid chromatography
- ICH
- International Conference on Harmonisation
- LC-MS/MS
- liquid chromatography tandem mass spectrometry
- LLOQ
- lower limit of quantitation
- LOD
- limit of detection
- LSC
- liquid scintillation counting
- PEG
- polyethylene glycol
- TRA
- total radioactivity
- ULN
- upper limit of normal
- Vz
- apparent volume of distribution.
- Received October 3, 2011.
- Accepted October 26, 2011.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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