Effect of food on the pharmacokinetics of TAS‐102 and its efficacy and safety in patients with advanced solid tumors

TAS‐102, a novel oral antitumor agent, consists of trifluridine and tipiracil hydrochloride (molar ratio, 1:0.5). We investigated the effects of food on trifluridine and tipiracil hydrochloride. The efficacy and safety of TAS‐102 were evaluated in patients with advanced solid tumors. We analyzed drug pharmacokinetics using a randomized, single‐dose, two‐treatment (fed versus fasting), two‐period, two‐sequence cross‐over design, followed by repeated administration. Patients were given single doses of TAS‐102 (35 mg/m²) in the pharmacokinetic phase and received twice‐daily doses of TAS‐102 in 28‐day cycles in the repeated administration phase for evaluating efficacy and safety. Food showed no effect on the area under the curve from 0 to 12 h or 0 h–infinity values of trifluridine following administration of TAS‐102 under fasting and fed conditions, whereas those of tipiracil hydrochloride decreased by approximately 40%. Maximum concentrations of both drugs decreased by approximately 40%, indicating that food influenced the absorption and bioavailability of trifluridine and tipiracil hydrochloride, respectively. During the repeated administration, stable disease was observed in nine patients with rectal, small‐cell lung, breast, thymic, duodenal, and prostate cancers. Major adverse events were neutropenia, leukopenia, anemia, and nausea. Postprandial administration was optimal for TAS‐102 because trifluridine's area under the curve was not changed by food, indicating that its clinical efficacy would not be affected. Additionally, postprandial administration was reasonable because the maximum concentration of trifluridine decreased in neutrophils, which correlated with previous studies. These results suggest that TAS‐102 would be an effective treatment for small‐cell lung, thymic, and colorectal cancers. This trial is registered with the Japan Pharmaceutical Information Center (no. JapicCTI‐111482).