Effect of high-fat diet on the pharmacokinetics and safety of flumatinib in healthy Chinese subjects

PURPOSE: To evaluate the effect of a high-fat diet on the pharmacokinetics and safety of flumatinib mesylate tablets in healthy Chinese subjects. METHODS: This study was a randomized, open-label, single-dose, two-period crossover trial in which subjects were randomly assigned to take 400 mg of flumatinib mesylate after a high-fat diet or a fasted state. After a 14-day washout period, the two groups were administered flumatinib mesylate under opposite conditions. Blood samples were collected at baseline 0 and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, and 96 h, respectively. Plasma concentrations of flumatinib and its metabolites (M1 and M3) were analyzed using liquid chromatography-mass spectrometry. Pharmacokinetic parameters were calculated using the non-compartmental module of the Phoenix WinNonlin Version 7.0 software. BE module of WinNonLin was used for statistical analysis of AUC(0–t), AUC(0–∞) and C(max) in plasma. RESULTS: Twelve healthy subjects, half male and half female, were enrolled. One subject withdrew due to a treatment-emergent adverse event. Eleven subjects were administered drugs on fasting and 12 were administered drugs after a high-fat diet. On high-fat diet/fasting, the least square geometric mean (LSGM) ratios of flumatinib, M1, M3, and their 90% confidence interval (CI) were as follows: for flumatinib, C(max), AUC(0–t) and AUC(0–∞) were 281.65% (225.80–351.31%), 167.43% (143.92–194.79%), and 166.87% (143.47–194.09%); for M1, C(max), AUC(0–t), and AUC(0–∞) were 188.59% (145.29–244.79), 163.94% (149.11–180.24%), and 164.48% (150.36–179.94%); for M3, C(max), AUC(0–t), and AUC(0–∞) were 63.47% (54.02–74.57%), 85.23% (74.72–97.22%), and 96.73% (86.63–108.02%). CONCLUSION: Among the subjects, oral administration of 400 mg of flumatinib was safe and well tolerated. High-fat diet significantly increases the exposure to flumatinib, therefore, fasting may be recommended. CLINICAL TRIAL REGISTRATION: The study was registered at chictr.org Identifier: ChiCTR-IIR-17013179.