James J Lee1,2, Jabed Seraj3, Kenichiro Yoshida3, Hirokazu Mizuguchi3, Sandra Strychor1, Jillian Fiejdasz4, Tyeler Faulkner4, Robert A Parise1, Patrick Fawcett4, Laura Pollice4, Scott Mason5, Jeremy Hague6, Marie Croft6, James Nugteren6, Charles Tedder7, Weijing Sun1,2, Edward Chu1,2, Jan Hendrik Beumer8,9,10. 1. Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Hillman Research Pavilion, Suite G27E, 5117 Centre Avenue, Pittsburgh, PA, 15213, USA. 2. Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. 3. Taiho Oncology Inc., Princeton, NJ, USA. 4. Clinical Research Services, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. 5. Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA. 6. Xceleron Inc., Germantown, MD, USA. 7. INC Research LLC, Raleigh, NC, USA. 8. Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Hillman Research Pavilion, Suite G27E, 5117 Centre Avenue, Pittsburgh, PA, 15213, USA. beumerj@gmail.com. 9. Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. beumerj@gmail.com. 10. Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA. beumerj@gmail.com.
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.
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.
Entities:
Keywords:
Excretion; Mass balance; Metabolism; Radiolabel; Trifluorothymidine
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