title: A Phase 1, Open-Label, Randomized, Crossover Study Evaluating the Bioavailability of TAS-102 (Trifluridine/Tipiracil) Tablets Relative to an Oral Solution Containing Equivalent Amounts of Trifluridine and Tipiracil.
abstract: TAS-102 (trifluridine/tipiracil) is composed of an antineoplastic thymidine-based nucleoside analogue trifluridine (FTD), and a thymidine phosphorylase inhibitor, tipiracil (TPI), at a molar ratio of 1:0.5 (weight ratio, 1:0.471). A phase 1 study evaluated relative bioavailability of TAS-102 tablets compared with an oral solution containing equivalent amounts of FTD and TPI. In an open-label, 2-sequence, 3-period, crossover bioavailability study (part 1), patients 18 years or older with advanced solid tumors were randomized to receive TAS-102 tablets (60 mg; 3 × 20-mg tablets) on day 1 and TAS-102 oral solution (60 mg) on days 8 and 15, or the opposite sequence. In an extension (part 2), all patients received TAS-102 tablets. Of the 46 patients treated in the crossover study, 38 were evaluable in the crossover bioavailability pharmacokinetic population. For area under the concentration-time curve (AUC)0-∞and AUC0-lastfor FTD and TPI, and maximum plasma concentration (Cmax) for TPI, the 90% confidence intervals (CIs) of the geometric mean ratios were within the 0.80 to 1.25 boundary for demonstration of bioequivalence; for FTD Cmax, the lower limit of the 90%CI was 0.786. The most frequently reported treatment-related grade 3 or 4 adverse events were neutropenia (7 patients) and decreased neutrophil count (3 patients). Although the lower limit of the 90%CI for the geometric mean ratio of FTD Cmaxwas slightly lower than 0.80, the bioavailability of the TAS-102 tablet is considered clinically similar to that of a TAS-102 oral solution. TAS-102 was well tolerated in this population of patients with advanced solid tumors.
authors.affiliation: Texas Oncology-Baylor University Medical Center, Dallas, Tx, USA.
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Becerra
authors.affiliation: Taiho Oncology, Inc, Princeton, NJ, USA.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Taiho Oncology, Inc, Princeton, NJ, USA.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Mizuguchi
authors.affiliation: Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, Fl, USA.
authors.forename: Manish
authors.initials: M
authors.lastname: Patel
authors.affiliation: The Translational Genomics Research Institute and HonorHealth, Scottsdale, Az, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Von Hoff
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D018592:Cross-Over Studies; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D011759:Pyrrolidines; D012996:Solutions; D013607:Tablets; D013941:Thymine; D016896:Treatment Outcome; D014271:Trifluridine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014498:Uracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D004338:Drug Combinations; D011759:Pyrrolidines; D012996:Solutions; D013607:Tablets; C000613803:trifluridine tipiracil drug combination; D014498:Uracil; D013941:Thymine; D014271:Trifluridine
keywords: TAS-102; trifluridine, tipiracil hydrochloride, bioavailability, bioequivalence