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Clinical Trial
. 2016 Mar;77(3):515-26.
doi: 10.1007/s00280-016-2965-2. Epub 2016 Jan 19.

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

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  8   9   10
Affiliations
Clinical Trial

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

James J Lee et al. Cancer Chemother Pharmacol. 2016 Mar.

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 [(14)C]-FTD, while patients in group B (N = 4) received 60 mg TAS-102 with 1000 nCi [(14)C]-TPI orally. Plasma, blood, urine, feces, and expired air (group A only) were collected up to 168 h and were analyzed for (14)C by accelerator mass spectrometry and analytes by LC-MS/MS.

Results: FTD: 59.8% of the (14)C 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 (14)C 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 (14)C-FTD was metabolized and mostly excreted in urine. The majority of (14)C-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: Excretion; Mass balance; Metabolism; Radiolabel; Trifluorothymidine.

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Figures

Figure 1
Figure 1
Chemical structures of 2-[14C]-FTD and 2-[14C]-TPI.
Figure 2
Figure 2
Mean (±SD) plasma concentration-time curves of [14C]-FTD derived total radioactivity (●, ng-FTD-equivalents/mL), unchanged FTD (○), and FTY (Δ) in 4 patients.
Figure 3
Figure 3
Mean (±SD) plasma concentration-time curves of [14C]-TPI derived total radioactivity (●, ng-TPI-equivalents/mL), and unchanged TPI (○) in 4 patients.
Figure 4
Figure 4
Mean (SD) urinary (□), fecal (○), expired air (Δ) and total (●) cumulative excretion (0–168 h) of [14C]-FTD related material (A) or [14C]-TPI related material (B) as part of TAS-102 in cancer patients (4 per cohort).
Figure 5
Figure 5
Radiochromatograms of (A) pooled plasma (0–168 h), (B) pooled urine (0–96 h), and (C) pooled feces (0–120 h) following a single oral administration of [14C]-FTD. Percentage radioactivity recovered represents the radioactivity in each fraction relative to the total radioactivity of the sample injected.
Figure 6
Figure 6
Radiochromatograms of (A) pooled plasma (0–96 h), (B) pooled urine (0–96 h), and (C) pooled feces (0–120 h) following a single oral administration of [14C]-TPI. Percentage radioactivity recovered represents the radioactivity in each fraction relative to the total radioactivity of the sample injected.
Figure 7
Figure 7
Proposed metabolism of FTD and TPI as components of TAS-102 in humans.
See this image and copyright information in PMC

References

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