Abstract
PurposeTo evaluate the effect of a high-fat diet on the pharmacokinetics and safety of flumatinib mesylate tablets in healthy Chinese subjects.MethodsThis 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 AUC0–t, AUC0–∞ and Cmax in plasma.ResultsTwelve 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, Cmax, AUC0–t and AUC0–∞ were 281.65% (225.80–351.31%), 167.43% (143.92–194.79%), and 166.87% (143.47–194.09%); for M1, Cmax, AUC0–t, and AUC0–∞ were 188.59% (145.29–244.79), 163.94% (149.11–180.24%), and 164.48% (150.36–179.94%); for M3, Cmax, AUC0–t, and AUC0–∞ were 63.47% (54.02–74.57%), 85.23% (74.72–97.22%), and 96.73% (86.63–108.02%).ConclusionAmong 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 registrationThe study was registered at chictr.org Identifier: ChiCTR-IIR-17013179.
Highlights
Chronic myelogenous leukemia (CML) called chronic granulocytic leukemia, is a slowly progressing blood and bone marrow disease that usually occurs during or after middle age,1 3 Vol.:(0123456789)Cancer Chemotherapy and Pharmacology (2020) 86:339–346 and rarely occurs in childhood [1]
This study aimed to determine the effect of a high-fat, high-calorie diet on the pharmacokinetics of flumatinib and to evaluate the safety of oral administration of flumatinib 400 mg in healthy subjects
M1 exposure was increased in presence of a high-fat meal, C max, AUC0–t and AUC0–∞ in plasma after high-fat diet (54.7 ± 25.5 ng h/ ml; 368 ± 177 ng h/ml; 390 ± 191 ng h/ml, respectively) were higher than that after fasting (27.2 ± 7.14 ng/ml: 231 ± 101 ng/ml; 243 ± 108 ng h/ml, respectively)
Summary
Chronic myelogenous leukemia (CML) called chronic granulocytic leukemia, is a slowly progressing blood and bone marrow disease that usually occurs during or after middle age,1 3 Vol.:(0123456789)Cancer Chemotherapy and Pharmacology (2020) 86:339–346 and rarely occurs in childhood [1]. A reciprocal chromosome translocation (9 and 22), called the Philadelphia chromosome, causes a constitutive activation of the BCR-ABL tyrosine kinase, leading to CML [2,3,4,5]. Current strategies for CML treatment involve the use of tyrosine kinase inhibitors, which can inhibit the BCR-ABL phosphorylation, thereby preventing the proliferation of cancer cells and activating subsequent apoptosis [2, 6,7,8,9]. Preclinical pharmacokinetic studies showed that, in rats and beagles, the maximum blood concentration could be reached in about 5 h after oral administration of the drug. The parent drug flumatinib was present in plasma, urine, and feces. The amide hydrolysis product (M3), which was inactive but approximately 30% of that of the parent drug in plasma [12]. Plasma concentrations of flumatinib, M1, and M3 were necessary to evaluate their circulating levels in humans
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