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To investigate the pharmacokinetic characteristics, safety and tolerability of single oral administration of trifluridine/tipiracil tablet in Chinese solid tumors under fasting and fed states, to evaluate the bioequivalence of the two formulations.
A randomized, open-label, two-formulation, two-sequence, four-cycle, repeated crossover design was used, with 30 subjects enrolled in both the fasting and fed groups, receiving a single oral dose of 60 mg of the test or reference formulation in each cycle. The concentrations of trifluridine and tipiracil in plasma were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Phoenix WinNonlin 8.3 and SAS 9.4 software were used for pharmacokinetic parameter and bioequivalence analysis.
Fasting group: The pharmacokinetic parameters of trifluridine were as follows. For the test preparation, Cmax was (6 711.36±1 641.92) ng·mL-1; AUC0-t was (14 216.19±4 420.98) h·ng·mL-1; AUC0-∞ was (14 432.88±4 613.02) h·ng·mL-1. For the reference preparation, Cmax was (6 332.20±1 606.03) ng·mL-1; AUC0-t was (14 393.26±4 070.13) h·ng·mL-1; AUC0-∞ was (14 636.58±4 285.74) h·ng·mL-1. The pharmacokinetic parameters of tipiracil were as follows. For the test preparation, Cmax was (140.73±44.39) ng·mL-1; AUC0-t was (491.99±149.66) h·ng·mL-1; AUC0-∞ was (499.49±150.62) h·ng·mL-1. For the reference preparation, Cmax was (142.70±42.64) ng·mL-1; AUC0-t was (505.43±135.58) h·ng·mL-1; AUC0-∞ was (513.42±137.70) h·ng·mL-1. Fed group: The pharmacokinetic parameters of trifluridine were as follows. For the test preparation, Cmax was (3 703.22±875.59) ng·mL-1; AUC0-t was (10 817.63±3 466.63) h·ng·mL-1; AUC0-∞ was (10 986.12±3 776.68) h·ng·mL-1. For the reference preparation, Cmax was (3 754.66±915.72) ng·mL-1; AUC0-t was (10 775.42±3 594.37) h·ng·mL-1; AUC0-∞ was (11 002.36±4 106.89) h·ng·mL-1. The pharmacokinetic parameters of tipiracil were as follows. For the test preparation, Cmax was (53.73±16.72) ng·mL-1; AUC0-t was (219.63±74.00) h·ng·mL-1; AUC0-∞ was (226.61±77.00) h·ng·mL-1. For the reference preparation, Cmax was (54.73±14.42) ng·mL-1; AUC0-t was (224.66±75.23) h·ng·mL-1; AUC0-∞ was (231.91±78.74) h·ng·mL-1. The geometric mean ratios and their 90% confidence intervals for the main pharmacokinetic parameters (Cmax, AUC0-t, AUC0-∞) of the test and reference formulations of trifluridine/tipiracil were all within the range of 80.00%-125.00%. Common adverse drug reactions in the fasting group includes sinus bradycardia and elevated alanine aminotransferase, while common adverse drug reactions in the fed group included decreased lymphocyte count and detection of urinary sediment. The incidence of adverse drug reactions in the fasting and fed conditions were 36.67% (11 cases / 30 cases) and 46.67% (14 cases / 30 cases), respectively. There were no serious adverse events occurred during the trials in the both group.
The test and reference formulations of trifluridine/tipiracil tablet are bioequivalent under both fasting and fed conditions, with good safety and tolerability.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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