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

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（SWR）<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SWR≥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Cmax、AUC0-t、AUC0-∞以及麦考酚酸Cmax的SWR大于0.294（分别为0.643 4、0.456 5、0.434 9和0.335 7），（YT－YR）2－θS2WR的单侧95%置信区间上限分别为－0.217 0、－0.118 8、－0.104 4和－0.043 7，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AUC0-t和AUC0-∞的SWR小于0.294（分别为0.090 9和0.108 4），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Cmax、AUC0-t和AUC0-∞的SWR大于0.294（分别为0.587 9、0.387 5和0.386 5），（YT－YR）2－θS2WR的单侧95%置信区间上限分别为－0.157 4、－0.085 2和－0.082 8，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Cmax、AUC0-t和AUC0-∞的SWR小于0.294（分别为0.260 9、0.112 2和0.127 5），几何均值比（T/R）的90%置信区间分别为91.28%～107.63%、97.39%～103.70%和96.72%～103.34%，结果均符合ABE的生物等效性判定标准。结论：吗替麦考酚酯胶囊的受试制剂与参比制剂在空腹及餐后条件下均生物等效。

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

AIM: 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 (SWR) 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 SWR for the PK parameter in the study is ≥0.294. RESULTS: Under fasting conditions, the SWR values for the Cmax, AUC0-t and AUC0-∞ of MMF and the Cmax of MPA were >0.294 (0.643 4, 0.456 5, 0.434 9, and 0.335 7, respectively). The 95%upper confidence bounds of (YT－YR)2－θS2WR for these PK parameters were －0.217 0, －0.118 8, －0.104 4, and －0.043 7, 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 SWR values for the AUC0-t and AUC0-∞ of MPA were <0.294 (0.090 9 and 0.108 4, 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 SWR values for the Cmax, AUC0-t and AUC0-∞ of MMF were >0.294 (0.587 9, 0.387 5, and 0.386 5, respectively). The 95%upper confidence bounds of (YT－YR)2－θS2WR for these PK parameters were －0.157 4, －0.085 2, and －0.082 8, respectively, and the point estimates of the test/reference geometric mean ratios for these PK parameters were 91.09%, 99.58%, and 99.58%, respectively. These results met the acceptance criteria of RSABE. Under fed conditions, the SWR values for the Cmax, AUC0-t and AUC0-∞ of MPA were <0.294 (0.260 9, 0.112 2, and 0.127 5, respectively). The 90%CIs of the test/reference geometric mean ratios for these PK parameters were 91.28%-107.63%, 97.39%-103.70%, and 96.72%-103.34%, respectively, which fell within the ABE acceptance range of 80.00%to 125.00%. CONCLUSION: The test and reference formulations of mycophenolate mofetil capsule are bioequivalent under fasting and fed conditions.