Abstract
BACKGROUND: This research aimed to compare the bioequivalence of a test formulation (regorafenib produced by Beijing SL Pharmaceutical Co., Ltd.) with a reference formulation (the original drug Stivarga(®)) in Chinese healthy subjects under fasting conditions and two postprandial states: after low-fat and high-fat meals. METHODS: The research design was a randomized, open-label, two-period crossover trial involving a single 40 mg oral dose. Three separate studies were conducted. Study 1 enrolled 64 subjects who were dosed under fasting conditions; Study 2 involved 76 subjects dosed after a low-fat breakfast; and Study 3 also involved 76 subjects dosed after a high-fat breakfast. Plasma concentrations of regorafenib and M-2 were determined using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The primary endpoints were the peak plasma concentration (C(max)), the area under the concentration-time curve from time 0 to 168 h (AUC(0-168h)), and the extrapolated area under the curve from time zero to infinity (AUC(0-∞)) of regorafenib, with pharmacokinetics (PK) parameters of the metabolite M-2 serving as reference data. RESULTS: The results showed that, under fasting, post-low-fat meal, and post-high-fat meal conditions, the 90% confidence intervals (CIs) of geometric mean ratios (GMRs) for C(max) of test to reference regorafenib were 96.39%-114.94%, 93.81%-106.67% and 94.23%-107.21%, respectively. For AUC(0-168h) were 88.40%-102.04%, 92.40%-102.97% and 92.50%-102.60%. For AUC(0-∞) were 85.86%-100.01%, 90.26%-101.79% and 90.15%-101.36%. All of these fell within the 80.00%-125.00% range, meeting the equivalence criteria. Food intake had some impact on the PK parameters of regorafenib, but the effect was minor. Administration of a single 40 mg dose of regorafenib to healthy subjects demonstrated good safety and tolerability. CONCLUSION: Under different dietary conditions, a single oral dose of 40 mg of generic drug regorafenib was bioequivalent to the original drug Stivarga(®) in healthy Chinese subjects, and the food effect was limited. CLINICAL TRIAL REGISTRATION: http://www.chinadrugtrials.org.cn/, identifier CTR20210575, CTR20210576, CTR20223278.