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Futibatinib, a selective, irreversible fibroblast growth factor receptor 1–4 inhibitor, was recently approved for FGFR2 rearrangement–positive cholangiocarcinoma. This Phase I study evaluated the mass balance and metabolic profile of 14C‐futibatinib single oral 20‐mg dose in healthy participants (n = 6). Futibatinib was rapidly absorbed; median time to peak drug concentration was 1.0 hours. The mean elimination half‐life in plasma was 2.3 hours for futibatinib, and 11.9 hours for total radioactivity. Mean recovery of total radioactivity was 70% of the dose, with 64% recovered in feces and 6% in urine. The major excretion route was fecal; negligible levels were excreted as parent futibatinib. Futibatinib was the most abundant plasma component, comprising 59% of circulating radioactivity (CRA). The most abundant metabolites were cysteinylglycine‐conjugated futibatinib in plasma (13% CRA) and reduction of desmethyl futibatinib in feces (17% of dose). In human hepatocytes, 14C‐futibatinib metabolites included glucuronide and sulfate of desmethyl futibatinib, whose formation was inhibited by 1‐aminobenzotriazole (a pan‐cytochrome P450 inhibitor), and glutathione‐ and cysteine‐conjugated futibatinib. These data indicate the primary metabolic pathways of futibatinib are O‐desmethylation and glutathione conjugation, with cytochrome P450 enzyme‐mediated desmethylation as the main oxidation pathway. 14C‐futibatinib was well tolerated in this Phase 1 study. [ABSTRACT FROM AUTHOR]

Futibatinib, an oral, irreversible fibroblast growth factor receptor (FGFR) 1–4 inhibitor, is being evaluated for FGFR‐aberrant tumors. Two open‐label phase 1 studies evaluated the effects of high‐fat, high‐calorie food and concomitant proton pump inhibitors (PPIs; lansoprazole) on single‐dose futibatinib (20 mg) pharmacokinetics and safety in healthy adults. In the food effect study (N = 17), subjects received futibatinib under fed and fasted conditions, separated by a 7‐day washout. In the PPI study (N = 20), subjects received futibatinib alone, underwent a 2‐day washout, and then received lansoprazole 60 mg once daily for 5 days, with futibatinib also administered on day 5. Under fed versus fasted conditions, futibatinib bioavailability was 11.2% lower (area under the plasma concentration–time curve from time 0 to infinity geometric mean ratio 88.8%; 90% confidence interval, 79.8%–98.9%), and median time to maximum plasma concentration was significantly delayed (4.0 vs 1.5 hours; P <.0001). There were no significant differences in futibatinib exposure between futibatinib plus lansoprazole and futibatinib alone. No serious adverse events occurred in either study. These findings suggest that food and PPIs are unlikely to have clinically meaningful impacts on futibatinib bioavailability. Thus, futibatinib may be used with or without food and concomitantly with acid‐reducing agents. [ABSTRACT FROM AUTHOR]

TAS‐114 is a dual deoxyuridine triphosphatase (dUTPase) and dihydropyrimidine dehydrogenase (DPD) inhibitor expected to widen the therapeutic index of capecitabine. Its maximum tolerated dose (MTD) was determined from a safety perspective in a combination study with capecitabine; however, its inhibitory effects on DPD activity were not assessed in the study. The dose justification to select its MTD as the recommended dose in terms of DPD inhibition has been required, but the autoinduction profile of TAS‐114 made it difficult. To this end, an approach using a population pharmacokinetic (PPK)/pharmacodynamic (PD) model incorporating autoinduction was planned; however, the utility of this approach in the dose justification has not been reported. Thus, the aim of this study was to demonstrate the utility of a PPK/PD model incorporating autoinduction in the dose justification via a case study of TAS‐114. Plasma concentrations of TAS‐114 from 185 subjects and those of the endogenous DPD substrate uracil from 24 subjects were used. A two‐compartment model with first‐order absorption with lag time and an enzyme turnover model were selected for the pharmacokinetic (PK) model. Moreover, an indirect response model was selected for the PD model to capture the changes in plasma uracil concentrations. Model‐based simulations provided the dose justification that DPD inhibition by TAS‐114 reached a plateau level at the MTD, whereas exposures of TAS‐114 increased dose dependently. Thus, the utility of a PPK/PD model incorporating autoinduction in the dose justification was demonstrated via this case study of TAS‐114. [ABSTRACT FROM AUTHOR]

Aims: Trifluridine/tipiracil (FTD/TPI) prolongs survival in refractory metastatic colorectal cancer, but limited data exist on its use in patients with hepatic impairment. This Phase I, open‐label, nonrandomized study investigated the safety, tolerability and pharmacokinetics of FTD/TPI in patients with advanced solid tumours (except breast cancer) and varying degrees of hepatic impairment, to provide dosing recommendations. Methods: Patients aged ≥18 years with advanced solid tumours and normal hepatic function, or mild, moderate or severe hepatic impairment according to National Cancer Institute criteria, were planned to be enrolled. Patients received FTD/TPI 35 mg/m2 orally twice daily on days 1–5 and 8–12 of each 28‐day cycle. Results: Twenty‐four patients were enrolled to the normal hepatic function (n = 8) and mild (n = 10) and moderate (n = 6) hepatic impairment cohorts. Overall, 12 patients (50.0%) had at least 1 adverse event leading to study discontinuation. In the moderate hepatic impairment cohort, 5 of 6 patients experienced grade ≥ 3 elevation in bilirubin. No patients with severe hepatic impairment were enrolled. FTD area under the curve at steady state decreased by 18% and 22% in the mild and moderate cohorts, respectively; however, no clear change was observed in TPI area under the curve. Conclusions: FTD/TPI can be safely administered in patients with normal hepatic function and mild hepatic impairment, with no initial dose adjustment. FTD/TPI is not recommended for use in patients with moderate hepatic impairment because of findings of grade 3 or 4 increased blood bilirubin. Therefore, FTD/TPI is not recommended for patients with moderate or severe hepatic impairment. [ABSTRACT FROM AUTHOR]

Purpose: Trifluridine (TFT) is an antitumor component of a novel nucleoside antitumor agent, TAS-102, which consists of TFT and tipiracil hydrochloride (thymidine phosphorylase inhibitor). Incorporation of TFT into DNA is a probable mechanism of antitumor activity and hematological toxicity. The objective of this study was to examine the TFT incorporation into tumor- and white blood cell-DNA, and to elucidate the mechanism of TFT-related effect and toxicity. TFT effect on the colony formation of mouse bone marrow cells was also investigated. Methods: Pharmacokinetics of TFT was determined in nude mice after single oral administration of TAS-102, while the antitumor activity and body weight change were evaluated in the tumor-bearing nude mice after multiple oral administrations for 2 weeks. TFT concentrations in the blood- and tumor-DNA were determined by LC/MS/MS. The colony formation was evaluated by CFU-GM assay. Results: TFT systemic exposure in plasma increased dose-dependently. The tumor growth rate and body weight gain decreased dose-dependently, but TFT concentrations in the DNA of tumor tissues and white blood cells increased dose-dependently. TFT inhibited colony formation of bone marrow cells in a concentration-dependent manner. Conclusions: A significant relationship between systemic exposure of TFT and pharmacological effects including the antitumor activity and body weight change was well explained by the TFT incorporation into DNA. TFT inhibited proliferations of mouse bone marrow cells and human colorectal carcinoma cells implanted to nude mice dose-dependently. The highest tolerable TFT exposure provides the highest antitumor activity, and the hematological toxicity may serve as a potential surrogate indicator of TAS-102 efficacy. [ABSTRACT FROM AUTHOR]