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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
Author(s) -
Becerra Carlos R.,
Yoshida Kenichiro,
Mizuguchi Hirokazu,
Patel Manish,
Hoff Daniel
Publication year - 2017
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.856
Subject(s) - bioavailability , cmax , bioequivalence , crossover study , pharmacokinetics , pharmacology , medicine , population , geometric mean , chemistry , placebo , mathematics , alternative medicine , environmental health , pathology , statistics
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 AUC 0‐last for FTD and TPI, and maximum plasma concentration (C max ) 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 C max , 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 C max was 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.