Journal
INVESTIGATIONAL NEW DRUGS
Volume 35, Issue 2, Pages 189-197Publisher
SPRINGER
DOI: 10.1007/s10637-016-0409-9
Keywords
Advanced solid tumors; Fluoropyrimidine; Pharmacokinetics; Trifluridine/tipiracil; Trifluridine
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Funding
- preparation of this publication was provided by Phase Five Communications-Taiho Oncology, Inc
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Background Trifluridine, a thymidine-based chemotherapeutic, has limited bioavailability after clinical administration as it is rapidly degraded via thymidine phosphorylase. An oral combination tablet combines trifluridine with a potent thymidine phosphorylase inhibitor, tipiracil hydrochloride. This study's objective was to evaluate whether trifluridine/tipiracil (TAS-102) administration increases trifluridine exposure vs trifluridine alone. Methods This open-label pharmacokinetic study randomly assigned patients with advanced solid tumors into two groups. On the morning of day 1, one group received a single 35 mg/m(2) dose of trifluridine/tipiracil and the other group received a single 35mg/ m(2) dose of trifluridine. Both groups received trifluridine/tipiracil 35 mg/m(2) on the evening of day 1, then twice daily on days 2-5 and 8-12 in a 28-day cycle. Results Twenty patients received an initial one-time dose of trifluridine alone and 19 other patients received an initial dose of trifluridine/tipiracil. Trifluridine area under the curve (AUC(0-last)) and maximum observed plasma concentrations (C-max) were approximately 37-and22- fold higher, respectively, with trifluridine/tipiracil vs trifluridine alone. Plasma concentrations of the major metabolite of trifluridine were lower following the administration of trifluridine/tipiracil vs trifluridine alone. Conclusion Tipiracil administered in combination with trifluridine significantly increased exposure to trifluridine compared with trifluridine alone.
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