枸橼酸托法替布片在中国健康受试者中的生物等效性研究

The Bioequivalence of Tofacitinib Citrate Tablet in Healthy Chinese Subjects

研究国产枸橼酸托法替布片在中国健康受试者中的药代动力学特征,评价国产受试制剂(T)与原研参比制剂(R,商品名:尚杰®)的生物等效性。采用空腹/餐后、随机、开放、两周期、双交叉试验设计。空腹试验和餐后试验分别入组30例健康受试者,男女兼有。入组的受试者随机分配至T-R或R-T给药序列组,每周期单次空腹或餐后口服枸橼酸托法替布片受试制剂或参比制剂5 mg/片。采用高效液相色谱-串联质谱法(HPLC-MS/MS)测定0~24 h不同时间点人血浆中托法替布浓度。采用Phoenix WinNonlin 7.0软件计算药代动力学参数(C_(max)、AUC_(0-t)、AUC_(0-∞)、T_(max)、t_(1/2)、λ_(z)、AUC_(_%Extrap)),并对主要药代动力学参数进行生物等效性评价。健康受试者空腹单次口服受试制剂及参比制剂枸橼酸托法替布片5 mg后,C_(max)、AUC_(0-t)、AUC_(0-∞)的算数均值分别为55.928和58.548 ng/mL,161.61和163.39 h·ng/mL,166.41和168.18 h·ng/mL。受试制剂与参比制剂C_(max)、AUC_(0-t)、AUC_(0-∞)几何均值的比值分别为95.48%,99.06%,99.09%;90%CI分别为89.83%~101.50%、95.92%~102.31%、95.91%~102.38%。健康受试者餐后口服受试制剂枸橼酸托法替布片及参比制剂枸橼酸托法替布片后,C_(max)、AUC_(0-t)、AUC_(0-∞)算数均值分别为43.998和40.741 ng/mL,159.52和162.72 h·ng/mL,165.04和169.00 h·ng/mL。受试制剂与参比制剂C_(max)、AUC_(0-t)、AUC_(0-∞)几何均值的比值分别为107.38%,98.61%,98.20%;90%CI分别为97.42%~118.35%,96.19%~101.09%,95.82%~100.62%。国产枸橼酸托法替布片与原研参比制剂(尚杰®)空腹或餐后状态下给药后,在中国健康受试者体内两制剂生物等效。

To study the pharmacokinetics(PK)of tofacitinib citrate tablet in healthy Chinese subjects,and evaluate the bioequivalence between the domestic test product(T)and the original reference product(R,trade name XELJANZ®),a randomized,open-label,two-period,crossover trial was conducted under fasted/fed of condition.Respectively,30 healthy Chinese subjects were enrolled in fasted trial or fed trial,both men and women.These subjects were randomly assigned to T-R or R-T sequence group,and to receive oral T or R tofacitinib citrate tablet(5 mg/tablet)during each treatment period under fasted or fed conditions.The concentration of tofacitinib in human plasma at different time points from 0 h to 24 h were determined by high performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS).Phoenix WinNonlin®7.0 program was used to calculate the PK parameters(C_(max)、AUC_(0-t)、AUC_(0-∞)、T_(max)、t_(1/2)、λ_(z)、AUC_(_%Extrap)),and evaluate bioequivalence of the main pharmacokinetic parameters.The mean values of PK parameters of T and R tofacitinib citrate tablet after single oral dose of 5 mg were C_(max)(55.928 and 58.548 ng/mL);AUC_(0-t)(161.61 and 163.39 h·ng/mL);and AUC_(0-∞)(166.41 and 168.18 h·ng/mL)under fasted condition.The T/R tofacitinib PK rations for C_(max),AUC_(0-t),AUC_(0-∞)were 95.48%,99.06%,and 99.09%,respectively.The corresponding 90%confidence interval(CI)were 89.83%~101.50%,95.92%~102.31%,and 95.91%~102.38%,respectively.The mean values of PK parameters of T and R tofacitinib citrate tablet after single oral dose of 5 mg were C_(max)(43.998 and 40.741 ng/mL);AUC_(0-t) (159.52 and 162.72 h·ng/mL);and AUC_(0-∞)(165.04 and 169.00 h·ng/mL)under fed condition.The T/R tofacitinib PK rations for C_(max),AUC_(0-t),AUC_(0-∞)were 107.38%,98.61%,and 98.20%,respectively.The corresponding 90%confidence interval(CI)were 97.42%~118.35%,96.19%~101.09%,and 95.82%~100.62%,respectively.The test and reference tofacitinib citrate tablet are bioequivalent in healthy Chinese subjects under fasted or fed conditions.