目的 考察在空腹、餐后状态下健康受试者口服瑞戈非尼片受试制剂或参比制剂体内瑞戈非尼的血药浓度和药动学参数，评价瑞戈非尼片的生物等效性和安全性。方法 采用单中心、单剂量、双制剂、随机、开放、双序列、双周期、自身交叉的试验设计，112例受试者分别在空腹（n＝64）或餐后（n＝48）口服40 mg的瑞戈非尼受试制剂或参比制剂，并在规定的时间点采集血样。以LC-MS/MS法测定血浆中瑞戈非尼的浓度，Phoenix WinNonlin 8.3软件的非房室模型计算各受试者的药动学参数，SAS 9.4软件进行临床安全性统计分析。结果 受试者空腹、餐后单次口服瑞戈非尼受试制剂及参比制剂后，药动学参数C_max分别是（599±245）、（569±209），（507±152）、（572±161）ng·mL^-1；AUC_0～t分别是（8 688±2 459）、（8 600±2 584），（12 203±3 973）、（13 495±3 910） h·ng·mL^-1； AUC_0～∞分别是（9 107±2 692）、（9 078±2 832），（12 834±4 422）、（14 121±4 391）h·ng·mL^-1。两制剂主要药动学参数的几何均值比均在等效范围内。空腹、餐后试验组的不良事件发生率分别是39.06%、41.67%，均未发生严重不良事件。结论 瑞戈非尼药时曲线出现二次达峰现象，认为与肝肠循环有关。高脂饮食可提高瑞戈非尼暴露量。受试制剂和参比制剂生物等效，单次服用安全且耐受性良好。

Objective To investigate the plasma concentrations and pharmacokinetic parameters of regorafenib in human body of healthy subjects taking the test or reference preparation of Regorafenib Tablets under fasting and fed conditions, and evaluate the bioequivalence and safety of two drugs. Methods A single center, single dose, two preparations, randomized, open-label, twosequence, two-cycle, and self-cross trial design was used. Tatolly 112 subjects were given the test or reference reagent of 40 mg Regorafenib Tablets in fasting (n = 64) and fed states (n = 48), respectively. And the vein blood was collected at specified timepoints. The concentrations of regorafenib in plasma were determined by LC-MS/MS method. The pharmacokinetic parameters of subjects were calculated by non-compartment model of Phoenix WinNonlin 8.3. And the statistical analyses of clinical safety were evaluated by SAS 9.4 software. Results After single oral administration of the test or reference regorafenib in fasting and fed states, subjects' pharmacokinetics parameters were as follows: C_max were (599 ±245), (569 ±209), (507 ±152) and (572 ±161) ng·mL^-1. AUC _0～t were (8 688 ±2 459), (8 600 ±2 584), (12 203 ±3 973) and (13 495 ±3 910) h·ng·mL^-1. AUC_{0 ～ ∞} were (9 107 ±2 692), (9 078 ±2 832), (12 834 ±4 422) and (14 121 ±4 391) h·ng·mL^-1. The geometric mean rations of the main pharmacokinetic parameters taking the two drugs were within the bioequivalence range. The incidences of adverse events under the fasting and fed conditions were 39.06% and 41.67%, respectively. There isn't serious adverse event. Conclusion There is a secondary peak in the concentration-time curves of regorafenib, which is thought to be related to hepatoenteric circulation. A high-fat diet increases the exposure of regorafenib. The test and reference preparations are bioequivalent, safe and well tolerated at a single dose.

R969.1