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01-03-2016 | Original Article

Human mass balance study of TAS-102 using ¹⁴C analyzed by accelerator mass spectrometry

Authors: James J. Lee, Jabed Seraj, Kenichiro Yoshida, Hirokazu Mizuguchi, Sandra Strychor, Jillian Fiejdasz, Tyeler Faulkner, Robert A. Parise, Patrick Fawcett, Laura Pollice, Scott Mason, Jeremy Hague, Marie Croft, James Nugteren, Charles Tedder, Weijing Sun, Edward Chu, Jan Hendrik Beumer

Published in: Cancer Chemotherapy and Pharmacology | Issue 3/2016

Abstract

Background

TAS-102 is an oral fluoropyrimidine prodrug composed of trifluridine (FTD) and tipiracil hydrochloride (TPI) in a 1:0.5 ratio. FTD is a thymidine analog, and it is degraded by thymidine phosphorylase (TP) to the inactive trifluoromethyluracil (FTY) metabolite. TPI inhibits degradation of FTD by TP, increasing systemic exposure to FTD.

Methods

Patients with advanced solid tumors (6 M/2 F; median age 58 years; PS 0–1) were enrolled on this study. Patients in group A (N = 4) received 60 mg TAS-102 with 200 nCi [¹⁴C]-FTD, while patients in group B (N = 4) received 60 mg TAS-102 with 1000 nCi [¹⁴C]-TPI orally. Plasma, blood, urine, feces, and expired air (group A only) were collected up to 168 h and were analyzed for ¹⁴C by accelerator mass spectrometry and analytes by LC–MS/MS.

Results

FTD: 59.8 % of the ¹⁴C dose was recovered: 54.8 % in urine mostly as FTY and FTD glucuronide isomers. The extractable radioactivity in the pooled plasma consisted of 52.7 % FTD and 33.2 % FTY. TPI: 76.8 % of the ¹⁴C dose was recovered: 27.0 % in urine mostly as TPI and 49.7 % in feces. The extractable radioactivity in the pooled plasma consisted of 53.1 % TPI and 30.9 % 6-HMU, the major metabolite of TPI.

Conclusion

Absorbed ¹⁴C-FTD was metabolized and mostly excreted in urine. The majority of ¹⁴C-TPI was recovered in feces, and the majority of absorbed TPI was excreted in urine. The current data with the ongoing hepatic and renal dysfunction studies will provide an enhanced understanding of the TAS-102 elimination profile.

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Title: Human mass balance study of TAS-102 using 14C analyzed by accelerator mass spectrometry
Authors: James J. Lee
Jabed Seraj
Kenichiro Yoshida
Hirokazu Mizuguchi
Sandra Strychor
Jillian Fiejdasz
Tyeler Faulkner
Robert A. Parise
Patrick Fawcett
Laura Pollice
Scott Mason
Jeremy Hague
Marie Croft
James Nugteren
Charles Tedder
Weijing Sun
Edward Chu
Jan Hendrik Beumer
Publication date: 01-03-2016
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 3/2016
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-016-2965-2

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Abstract

Background

Methods

Results

Conclusion

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