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

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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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Acknowledgments

We thank the patients and their family members for their dedication and commitment to this clinical study. We thank the nursing staff of the University of Pittsburgh Clinical Translational Research Center for their invaluable assistance. This work was supported by Taiho Oncology, Inc., and NIH/NCRR/CTSA Grant UL1 RR024153. This project used the UPCI Cancer Pharmacokinetics and Pharmacodynamics Facility (CPPF) and was supported in part by award P30CA047904. We would like to thank the following individuals and organizations for their input in the various stages of this project: Manuel Aivado, Brian Kiesel, Milind Narurkar, Mark Seymour, Dennis Swanson, Tracy Topp, Erin Sternberg, and JCL Bioassay USA Inc. The authors were responsible for all content and editorial decisions and received no honoraria related to the development of this publication. All authors contributed to the research, writing, and reviewing of all drafts of this publication, and all authors approved the final draft prior to submission.

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Authors and Affiliations

  1. Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Hillman Research Pavilion, Suite G27E, 5117 Centre Avenue, Pittsburgh, PA, 15213, USA

    James J. Lee, Sandra Strychor, Robert A. Parise, Weijing Sun, Edward Chu & Jan Hendrik Beumer

  2. Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    James J. Lee, Weijing Sun, Edward Chu & Jan Hendrik Beumer

  3. Taiho Oncology Inc., Princeton, NJ, USA

    Jabed Seraj, Kenichiro Yoshida & Hirokazu Mizuguchi

  4. Clinical Research Services, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    Jillian Fiejdasz, Tyeler Faulkner, Patrick Fawcett & Laura Pollice

  5. Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA

    Scott Mason

  6. Xceleron Inc., Germantown, MD, USA

    Jeremy Hague, Marie Croft & James Nugteren

  7. INC Research LLC, Raleigh, NC, USA

    Charles Tedder

  8. Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA

    Jan Hendrik Beumer

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  1. James J. Lee
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Correspondence to Jan Hendrik Beumer.

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Lee, J.J., Seraj, J., Yoshida, K. et al. Human mass balance study of TAS-102 using 14C analyzed by accelerator mass spectrometry. Cancer Chemother Pharmacol 77, 515–526 (2016). https://doi.org/10.1007/s00280-016-2965-2

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  • DOI: https://doi.org/10.1007/s00280-016-2965-2

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