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

This study was a single-center, randomized, open-label, two-period, crossover design to evaluate the effects of a high-fat diet on the pharmacokinetics of flumatinib in healthy subjects.

The subjects were randomized 24 h in advance in one of the two following groups. Group A: at least 10 h after fasting, oral flumatinib administration of 400 mg (2 tablets, day 1, first dose); the washout period was 14 days, half an hour after high-fat diet (timed from the start of diet) oral flumatinib administration of 400 mg (2 tablets, day 15,second dose). Subjects in group B followed the opposite administration sequence from those in group A. In groups A and B, the high-fat diet contained 800 ~ 1000Kcal (about 50% from fat) (meal composition is detailed Table 1).

Blood samples for pharmacokinetic (PK) evaluation were collected at 0 h before the initiation of dosing (pre-dose), and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, and 96 h after dosing. Blood samples were centrifuged at 2000g for 10 min at 4 ℃. Centrifugation was completed within 60 min after sample collection. The plasma was stored at − 70 °C for further analysis. Plasma concentrations of flumatinib and its main metabolites (M1 and M3) were determined using liquid chromatography-mass spectrometry (LC–MS/MS) [20].

All subjects who participated in the study were included in the safety analysis. Safety was evaluated by vital signs, physical examination, ECG, laboratory examination, adverse events (AEs), and combined medication. All adverse events that occurred during the trial were classified into mild, moderate and severe levels based on NCI CTCAE v4.03.

Phoenix WinNonlin Version 7.0 (Pharsight Corporation, Sunnyvale, CA, USA) software was used to calculate the pharmacokinetic parameters (T_max, C_max, AUC_0–t, AUC_0–∞, t_1/2, V/F, CL/F) of flumatinib and its main metabolites using a non-compartmental method (NCA module). Linear Up Log Down trapezoidal method was used for AUC calculation. The BE module of WinNonLin was used to analyze AUC_0–t, AUC_0–∞, and C_max of flumatinib in fed and fasting states after logarithmic conversion. The treatment group (fasting, high-fat diet), the treatment sequence (A, B), and treatment phase were fixed effects in the model, and the subjects nested in the sequence were random effects. The adjusted mean difference (fasting/high-fat diet) and its 90% confidence interval estimated by the model, were taken as the negative number to obtain the corresponding PK parameter geometric mean ratio (postprandial/fasting), to estimate its 90% confidence interval, and to evaluate the effect of a high-fat diet on the pharmacokinetics of flumatinib.

The mean plasma concentration versus time profiles of flumatinib, M1 and M3 in healthy Chinese subjects receiving a single oral dose of flumatinib mesylate tablet (400 mg) are shown in Fig. 2. The C_max, AUC_0–t, AUC_0–∞, and the secondary pharmacokinetic endpoints (T_max, T_1/2, V/F, CL/F and MRT) of flumatinib, M1 and M3 are shown in Table 3. Mean (± standard deviation) C_max, AUC_0–t, AUC_0–∞ of flumatinib in plasma after a high-fat diet (132 ± 54.5 ng/ml; 1260 ± 582 ng h/ml; 1277 ± 586 ng h/ml, respectively) were higher than on fasting (50.7 ± 32.5 ng/ml; 832 ± 566 ng h/ml; 847 ± 572 ng·h/ml, respectively). M1 exposure was also increased in presence of a high-fat meal, C_max, AUC_0–t and AUC_0–∞ 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). CL/F, V/F, and MRT in plasma after high-fat diet (661 ± 380 L/h; 11700 ± 5130 L; 19.2 ± 3.37 h, respectively) were lower than that after fasting (399 ± 229 L/h; 8470v± 4130 L, 17.2 ± 3.66 h, respectively).

The least-square geometric mean (LSGM) ratio of flumatinib, M1, M3 and their 90% confidence interval (CI) after high-fat diet/fasting are shown in Table 4. The Cmax of flumatinib in plasma after a high-fat diet had nearly tripled over that in the fasted state, and the Cmax of M1 increased 1.9-fold. The AUC_0–t and AUC_0–∞ of flumatinib and M1 increased 1.6-fold. Except for the 90%CI of M3 AUC_0–∞ which was within 80.00–125.00%, the other parameters of flumatinib and metabolites M1 and M3 had 90% CI outside 80.00–125.00%. This indicated that a high-fat diet had a significant effect on pharmacokinetic of flumatinib, M1, and M3. And a high-fat diet can increase the peak concentration and systemic exposure of flumatinib and M1.

Safety evaluations were performed in all subjects (n = 12). In the fasting group, there were nine cases of treatment-emergent adverse event (TEAE) (81.8%) and eight (72.7%) were related to the study drug. (Table 5). In the high-fat diet group, there were ten cases of TEAE (83.3%) and seven (58.3%) were related to the study drug. Except for one case of moderate acute gastroenteritis (withdrawal), the other TEAEs were mild. Acute gastroenteritis was completely relieved after treatments, including anti-infection, spasmolysis, antiemesis and acid suppression. Other mild adverse events disappeared without any treatment. The TEAE related to the drug included mild gastrointestinal symptoms (abdominal pain, diarrhea, and abdominal distension) and mild laboratory abnormalities (alanine aminotransferase, blood magnesium, and uric acid slightly increase).

The results of the Phase Ia clinical trial showed that there were significant differences in AUC_0-t and C_max of flumatinib and M1 between fasting and high-fat diet (p < 0.05), implying the oral absorption of flumatinib could be promoted by postprandial administration. These are similar to the results of our study in healthy people. This is consistent with a report on a similar drug (ivosidenib), in which a 98% increase in Cmax was observed in healthy subjects who were given the drug after a high-fat diet, as compared to the fasting [21]. The increase in bioavailability of lapatinib after low-fat and high-fat diet were 167% and 325%, respectively [22]. The reasons for our results are as follows, First, a high-fat diet increases the secretion of bile acid (BA), especially secondary BA, such as deoxycholic acid and lithocholic acid, which slows gastric emptying and weakens intestinal peristalsis, resulting in prolonged retention time of flumatinib in the gastrointestinal tract, thereby increasing absorption [23]. Second, flumatinib is a lipophilic drug, thus, a high-fat diet can increase the solubility of flumatinib, thereby promoting drug absorption and increasing its (relative) bioavailability [24]. The C_max and AUC_0–t of M3 after a high-fat diet was decerased compared with that of fasting. This may be due to poor detection sensitivity as the M3 proportion is small. Alternatively, postprandial administration had less effect on the parent drug to M3 metabolic pathway. CL/F and V/F of flumatinib are huge because flumatinib has a low bioavailability. First, based on the BCS(Biopharmaceutics Classification System) Guidance of the year 2000, flumatinib is classified as BCS Class III. Second, a large amount of unmetabolized parent drug was detected in the feces after oral administration, which may be related to oral malabsorption caused by the low-permeability of flumatinib. Third, the bioavailability of flumatinib increased after high-fat meal, indicating that high-fat diet improved the low- permeability of flumatinib and improved the low-bioavailability of flumatinib, so the CL/F and V/F of postprandial administration decreased correspondingly (Fig. 3).

The incidence of TEAE was similar between the two conditions, while the incidence of TEAE related to the study drug after high-fat diet was better than that of fasting. However, it is uncertain whether the safety of the drug after a high-fat diet is better than that after fasting due to the small sample size. TEAEs including mild gastrointestinal symptoms and mild laboratory abnormalities are similar to most of the adverse reactions in oncology. For example, the FDA labels warnings of the potential for liver toxicity and rare cases of fatal liver failure [25].

The combination of a high-fat diet with flumatinib increased the bioavailability of flumatinib and M1. So taking it with food (which may increase its bioavailability) may have clinical implications, such as toxic reactions and increased accumulation. In this study, there was no significant increase in adverse reactions after a high-fat diet as compared with fasting. Combined with the clinical data of Phase II and III, the exposure and bioavailability of flumatinib after a high-fat diet was increased, so postprandial administration may have potential risks. The exposure and bioavailability of nilotinib, which is a BCR-ABL tyrosinase inhibitor, increased significantly after administration with food compared with fasting. In healthy subjects, C_max and AUC were reported to be 112% and 82% higher when taken with food than fasting [26]. Therefore, the marketing instructions for nilotinib indicate that it should be taken on an empty stomach. Therefore, in terms of the selection of the drug administration recommended in the later stage of clinical practice, flumatinib may only be taken on an empty stomach without food.