目的 考察在空腹、餐后狀態(tài)下健康受試者口服瑞戈非尼片受試制劑或參比制劑體內(nèi)瑞戈非尼的血藥濃度和藥動學(xué)參數(shù)，評價瑞戈非尼片的生物等效性和安全性。方法 采用單中心、單劑量、雙制劑、隨機、開放、雙序列、雙周期、自身交叉的試驗設(shè)計，112例受試者分別在空腹（n＝64）或餐后（n＝48）口服40 mg的瑞戈非尼受試制劑或參比制劑，并在規(guī)定的時間點采集血樣。以LC-MS/MS法測定血漿中瑞戈非尼的濃度，Phoenix WinNonlin 8.3軟件的非房室模型計算各受試者的藥動學(xué)參數(shù)，SAS 9.4軟件進行臨床安全性統(tǒng)計分析。結(jié)果 受試者空腹、餐后單次口服瑞戈非尼受試制劑及參比制劑后，藥動學(xué)參數(shù)C_max分別是（599±245）、（569±209），（507±152）、（572±161）ng·mL^-1；AUC_0～t分別是（8 688±2 459）、（8 600±2 584），（12 203±3 973）、（13 495±3 910） h·ng·mL^-1； AUC_0～∞分別是（9 107±2 692）、（9 078±2 832），（12 834±4 422）、（14 121±4 391）h·ng·mL^-1。兩制劑主要藥動學(xué)參數(shù)的幾何均值比均在等效范圍內(nèi)?？崭埂⒉秃笤囼灲M的不良事件發(fā)生率分別是39.06%、41.67%，均未發(fā)生嚴重不良事件。結(jié)論 瑞戈非尼藥時曲線出現(xiàn)二次達峰現(xiàn)象，認為與肝腸循環(huán)有關(guān)。高脂飲食可提高瑞戈非尼暴露量。受試制劑和參比制劑生物等效，單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