Cancer Chemotherapy and Pharmacology

, Volume 77, Issue 3, pp 515–526 | Cite as

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

  • 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
Original Article

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.

Keywords

Mass balance Trifluorothymidine Radiolabel Excretion Metabolism 

References

  1. 1.
    Tanaka N et al (2014) Repeated oral dosing of TAS-102 confers high trifluridine incorporation into DNA and sustained antitumor activity in mouse models. Oncol Rep 32(6):2319–2326PubMedCentralPubMedGoogle Scholar
  2. 2.
    Temmink OH et al (2007) Therapeutic potential of the dual-targeted TAS-102 formulation in the treatment of gastrointestinal malignancies. Cancer Sci 98(6):779–789CrossRefPubMedGoogle Scholar
  3. 3.
    Emura T et al (2004) A novel antimetabolite, TAS-102 retains its effect on FU-related resistant cancer cells. Int J Mol Med 13(4):545–549PubMedGoogle Scholar
  4. 4.
    Emura T et al (2004) A novel combination antimetabolite, TAS-102, exhibits antitumor activity in FU-resistant human cancer cells through a mechanism involving FTD incorporation in DNA. Int J Oncol 25(3):571–578PubMedGoogle Scholar
  5. 5.
    Emura T et al (2005) Potentiation of the antitumor activity of alpha, alpha, alpha-trifluorothymidine by the co-administration of an inhibitor of thymidine phosphorylase at a suitable molar ratio in vivo. Int J Oncol 27(2):449–455PubMedGoogle Scholar
  6. 6.
    Overman MJ et al (2008) Phase I clinical study of three times a day oral administration of TAS-102 in patients with solid tumors. Cancer Investig 26(8):794–799CrossRefGoogle Scholar
  7. 7.
    Overman MJ et al (2008) Phase 1 study of TAS-102 administered once daily on a 5-day-per-week schedule in patients with solid tumors. Investig New Drugs 26(5):445–454CrossRefGoogle Scholar
  8. 8.
    Hong DS et al (2006) Phase I study to determine the safety and pharmacokinetics of oral administration of TAS-102 in patients with solid tumors. Cancer 107(6):1383–1390CrossRefPubMedGoogle Scholar
  9. 9.
    Yoshino T et al (2012) TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol 13(10):993–1001CrossRefPubMedGoogle Scholar
  10. 10.
    Mayer RJ et al (2015) Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 372(20):1909–1919CrossRefPubMedGoogle Scholar
  11. 11.
    Kotani D, Fukuoka S, Yoshino T (2015) Efficacy of TAS-102. Gan To Kagaku Ryoho 42(1):1–5PubMedGoogle Scholar
  12. 12.
    Beumer JH et al (2007) Human mass balance study of the novel anticancer agent ixabepilone using accelerator mass spectrometry. Investig New Drugs 25(4):327–334CrossRefGoogle Scholar
  13. 13.
    Graham RA et al (2011) A single dose mass balance study of the Hedgehog pathway inhibitor vismodegib (GDC-0449) in humans using accelerator mass spectrometry. Drug Metab Dispos 39(8):1460–1467CrossRefPubMedGoogle Scholar
  14. 14.
    U.S. Department of Health and Human Services Food and Drug Administration (2001) Guidance for industry-bioanalytical method validation. U.S. Department of Health and Human Services; Food and Drug Administration; Center for Drug Evaluation; and Research Center for Veterinary MedicineGoogle Scholar
  15. 15.
    Hamilton RA, Garnett WR, Kline BJ (1981) Determination of mean valproic acid serum level by assay of a single pooled sample. Clin Pharmacol Ther 29(3):408–413CrossRefPubMedGoogle Scholar
  16. 16.
    Doi T et al (2012) Phase I study of TAS-102 treatment in Japanese patients with advanced solid tumours. Br J Cancer 107(3):429–434PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Khalili P et al (2002) Pharmacokinetics and metabolism of the novel synthetic C-nucleoside, 1-(2-deoxy-beta-d-ribofuranosyl)-2,4-difluoro-5-iodobenzene: a potential mimic of 5-iodo-2′-deoxyuridine. Biopharm Drug Dispos 23(3):105–113CrossRefPubMedGoogle Scholar
  18. 18.
    Zhou L et al (2010) Disposition of [1′-(14)C]stavudine after oral administration to humans. Drug Metab Dispos 38(4):655–666CrossRefPubMedGoogle Scholar
  19. 19.
    Desmoulin F et al (2007) A glucuronidation pathway of capecitabine occurs in rats but not in mice and humans. Drug Metab Lett 1(2):101–107CrossRefPubMedGoogle Scholar
  20. 20.
    Desmoulin F et al (2002) Metabolism of capecitabine, an oral fluorouracil prodrug: (19)F NMR studies in animal models and human urine. Drug Metab Dispos 30(11):1221–1229CrossRefPubMedGoogle Scholar
  21. 21.
    Nicolas F et al (1995) Comparative metabolism of 3′-azido-3′-deoxythymidine in cultured hepatocytes from rats, dogs, monkeys, and humans. Drug Metab Dispos 23(3):308–313PubMedGoogle Scholar
  22. 22.
    Good SS et al (1990) Isolation and characterization of an ether glucuronide of zidovudine, a major metabolite in monkeys and humans. Drug Metab Dispos 18(3):321–326PubMedGoogle Scholar
  23. 23.
    Dexter DL et al (1972) The clinical pharmacology of 5-trifluoromethyl-2′-deoxyuridine. Cancer Res 32(2):247–253PubMedGoogle Scholar
  24. 24.
    Shields AF et al (1996) Analysis of 2-carbon-11-thymidine blood metabolites in PET imaging. J Nucl Med 37(2):290–296PubMedGoogle Scholar
  25. 25.
    Beumer JH, Beijnen JH, Schellens JH (2006) Mass balance studies, with a focus on anticancer drugs. Clin Pharmacokinet 45(1):33–58CrossRefPubMedGoogle Scholar
  26. 26.
    Ghoos Y et al (1988) Measurement of 13C-glucose oxidation rate using mass spectrometric determination of the CO2: Ar ratio and spirometry. Biomed Environ Mass Spectrom 15(8):447–451CrossRefPubMedGoogle Scholar
  27. 27.
    Rogers WI et al (1969) The fate of 5-trifluoromethyl-2′-deoxyuridine in monkeys, dogs, mice, and tumor-bearing mice. Cancer Res 29(4):953–961PubMedGoogle Scholar
  28. 28.
    Heidelberger C, Boohar J, Kampschroer B (1965) Fluorinated pyrimidines. Xxiv. In vivo metabolism of 5-trifluoromethyluracil-2-C-14 and 5-trifluoromethyl-2′-deoxyuridine-2-C-14. Cancer Res 25:377–381PubMedGoogle Scholar
  29. 29.
    Andersen JT et al (2014) Extending serum half-life of albumin by engineering neonatal Fc receptor (FcRn) binding. J Biol Chem 289(19):13492–13502PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Hammond TG et al (2014) Mass spectrometric characterization of circulating covalent protein adducts derived from a drug acyl glucuronide metabolite: multiple albumin adductions in diclofenac patients. J Pharmacol Exp Ther 350(2):387–402PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Meng X et al (2013) Detection of drug bioactivation in vivo: mechanism of nevirapine–albumin conjugate formation in patients. Chem Res Toxicol 26(4):575–583CrossRefPubMedGoogle Scholar
  32. 32.
    Ariza A et al (2012) Protein haptenation by amoxicillin: high resolution mass spectrometry analysis and identification of target proteins in serum. J Proteomics 77:504–520CrossRefPubMedGoogle Scholar
  33. 33.
    Wang J et al (2010) Characterization of HKI-272 covalent binding to human serum albumin. Drug Metab Dispos 38(7):1083–1093CrossRefPubMedGoogle Scholar
  34. 34.
    Shipkova M et al (2002) Pharmacokinetics and protein adduct formation of the pharmacologically active acyl glucuronide metabolite of mycophenolic acid in pediatric renal transplant recipients. Ther Drug Monit 24(3):390–399CrossRefPubMedGoogle Scholar
  35. 35.
    Wang M, Dickinson RG (2000) Bile duct ligation promotes covalent drug-protein adduct formation in plasma but not in liver of rats given zomepirac. Life Sci 68(5):525–537CrossRefPubMedGoogle Scholar
  36. 36.
    Georges H et al (1999) Glycation of human serum albumin by acylglucuronides of nonsteroidal anti-inflammatory drugs of the series of phenylpropionates. Life Sci 65(12):PL151-6CrossRefPubMedGoogle Scholar
  37. 37.
    Benet LZ et al (1993) Predictability of the covalent binding of acidic drugs in man. Life Sci 53(8):PL141-6CrossRefPubMedGoogle Scholar
  38. 38.
    Klaassen CD (ed) (2008) Casarett and Doull’s toxicology: the basic science of Poisons, 7th edn. McGraw-Hill, New York, p 1309Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • James J. Lee
    • 1
    • 2
  • Jabed Seraj
    • 3
  • Kenichiro Yoshida
    • 3
  • Hirokazu Mizuguchi
    • 3
  • Sandra Strychor
    • 1
  • Jillian Fiejdasz
    • 4
  • Tyeler Faulkner
    • 4
  • Robert A. Parise
    • 1
  • Patrick Fawcett
    • 4
  • Laura Pollice
    • 4
  • Scott Mason
    • 5
  • Jeremy Hague
    • 6
  • Marie Croft
    • 6
  • James Nugteren
    • 6
  • Charles Tedder
    • 7
  • Weijing Sun
    • 1
    • 2
  • Edward Chu
    • 1
    • 2
  • Jan Hendrik Beumer
    • 1
    • 2
    • 8
  1. 1.Cancer Therapeutics ProgramUniversity of Pittsburgh Cancer InstitutePittsburghUSA
  2. 2.Division of Hematology-Oncology, Department of MedicineUniversity of Pittsburgh School of MedicinePittsburghUSA
  3. 3.Taiho Oncology Inc.PrincetonUSA
  4. 4.Clinical Research ServicesUniversity of Pittsburgh Cancer InstitutePittsburghUSA
  5. 5.Department of RadiologyUniversity of PittsburghPittsburghUSA
  6. 6.Xceleron Inc.GermantownUSA
  7. 7.INC Research LLCRaleighUSA
  8. 8.Department of Pharmaceutical SciencesUniversity of Pittsburgh School of PharmacyPittsburghUSA

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