吗替麦考酚酯胶囊在中国健康男性受试者空腹及餐后状态下的完全重复交叉设计的生物等效性研究  

A fully replicated crossover bioequivalence study of mycophenolate mofetil capsules in Chinese healthy male subjects under fasting and fed conditions

作　　者：史革鑫 崇锐 贺坤 吴海棠 周宇 顿中军 温清 张继国 张荣 SHI Gexin;CHONG Rui;HE Kun;WU Haitang;ZHOU Yu;DUN Zhongjun;WEN Qing;ZHANG Jiguo;ZHANG Rong(School of Pharmaceutical Sciences,Shandong First Medical University,Jinan 250000,Shandong,China;Central Hospital Affiliated to Shandong First Medical University,Jinan 250000,Shandong,China;Jiangsu Simcere Pharmaceutical Co.,Ltd.,Nanjing 21000,Jiangsu,China;State Key Laboratory of Translational Medicine and Innovative Drug Development,Nanjing 210000,Jiangsu,China;Shanghai Xihua Scientific Co.,Ltd.,Shanghai 200000,China;Beijing Trust Medical Consulting Co.,Ltd.,Beijing 100000,China)

机构地区：[1]山东第一医科大学药学院,山东济南250000 [2]山东第一医科大学附属中心医院,山东济南250000 [3]江苏先声药业有限公司,江苏南京210000 [4]转化医学与创新药物国家重点实验室,江苏南京210000 [5]上海熙华检测技术服务股份有限公司,上海200000 [6]北京信立达医药科技有限公司,北京100000

出　　处：《中国临床药理学与治疗学》2022年第11期1255-1263,共9页Chinese Journal of Clinical Pharmacology and Therapeutics

摘　　要：目的:评价吗替麦考酚酯胶囊受试制剂与参比制剂在中国健康男性受试者空腹及餐后状态下的生物等效性。方法:空腹试验和餐后试验各入组40例中国健康男性受试者,均采用两制剂、两序列、四周期、完全重复交叉设计。受试者于每周期单剂量口服0.25 g吗替麦考酚酯胶囊受试制剂或参比制剂。采用液相色谱-串联质谱(LC-MS/MS)法测定血浆中吗替麦考酚酯和代谢产物麦考酚酸的浓度。通过Phoenix WinNonlin 8.0软件采用非房室模型计算药动学参数,使用SAS 9.4软件进行统计分析。对于参比制剂的个体内标准差(S_(WR))<0.294的药动学参数采用平均生物等效性(ABE)方法进行生物等效性评价,对于S_(WR)≥0.294的药动学参数采用参比制剂校正的平均生物等效性(RSABE)方法进行生物等效性评价。结果:在空腹试验中,吗替麦考酚酯C_(max)、AUC_(0-t)、AUC_(0-∞)以及麦考酚酸C_(max)的S_(WR)大于0.294(分别为0.6434、0.4565、0.4349和0.3357),(Y_(T)-Y_(R))2-θS_(WR)^(2)的单侧95%置信区间上限分别为-0.2170、-0.1188、-0.1044和-0.0437,几何均值比(T/R)的点估计值分别为91.73%、98.95%、98.13%和92.09%,结果均符合RSABE的生物等效性判定标准。在空腹试验中,麦考酚酸AUC_(0-t)和AUC_(0-∞)的S_(WR)小于0.294(分别为0.0909和0.1084),几何均值比(T/R)的90%置信区间分别为95.49%~100.07%和95.10%~100.26%,结果均符合ABE的生物等效性判定标准。在餐后试验中,吗替麦考酚酯C_(max)、AUC_(0-t)和AUC_(0-∞)的S_(WR)大于0.294(分别为0.5879、0.3875和0.3865),(Y_(T)-Y_(R))2-θS_(WR)^(2)的单侧95%置信区间上限分别为-0.1574、-0.0852和-0.0828,几何均值比(T/R)的点估计值分别为91.09%、99.58%和99.58%,结果均符合RSABE的生物等效性判定标准。在餐后试验中,麦考酚酸C_(max)、AUC_(0-t)和AUC_(0-∞)的S_(WR)小于0.294(分别为0.2609、0.1122和0.1275),几何均值比(T/R)的90%置信区间分别为91.28%~107.63%、97.39%~1AIM:To evaluate the bioequivalence of the test and reference formulations of mycophenolate mofetil capsule in Chinese healthy male subjects under fasting and fed conditions.METHODS:This was a 2-treatment,2-sequence,4-period,fully replicated crossover study that included 80 Chinese healthy male subjects(40 subjects in the fasting group and 40 subjects in the fed group,respectively).Subjects were assigned to receive a single oral administration of the test or reference formulation at a dose of 0.25 g in each period.The plasma concentration of mycophenolate mofetil(MMF)and metabolite mycophenolic acid(MPA)were analyzed by LC-MS/MS.The major pharmacokinetic parameters of MMF and MPA were calculated using non-compartmental analysis by WinNonlin 8.0.The statistical analysis was performed by SAS 9.4.Average bioequivalence(ABE)analysis was applied where it has been demonstrated that the within-subject standard deviation of the reference formulation(S_(WR))for the PK parameter in the study is<0.294,while reference-scaled average bioequivalence(RSABE)analysis was applied where it has been demonstrated that the S_(WR) for the PK parameter in the study is≥0.294.RESULTS:Under fasting conditions,the S_(WR) values for the C_(max),AUC_(0-t) and AUC_(0-∞)of MMF and the C_(max) of MPA were>0.294(0.6434,0.4565,0.4349,and 0.3357,respectively).The 95%upper confidence bounds of(Y_(T)-Y_(R))2-θS_(WR)^(2) for these PK parameters were-0.2170,-0.1188,-0.1044,and-0.0437,respectively,and the point estimates of the test/reference geometric mean ratios for these PK parameters were 91.73%,98.95%,98.13%,and 92.09%,respectively.These results met the acceptance criteria of RSABE.Under fasting conditions,the S_(WR) values for the AUC_(0-t) and AUC_(0-∞)of MPA were<0.294(0.0909 and 0.1084,respectively).The 90%CIs of the test/reference geometric mean ratios for these PK parameters were 95.49%-100.07%and 95.10%-100.26%,respectively,which fell within the ABE acceptance range of 80.00%to 125.00%.Under fed conditions,the S_(WR) values for the C_(

关 键 词：吗替麦考酚酯 麦考酚酸 药代动力学 高变异 生物等效性 平均生物等效性 参比制剂校正的平均生物等效性 

分 类 号：R969.4[医药卫生—药理学]