【摘要】 目的 研究富马酸丙酚替诺福韦及其代谢物替诺福韦在中国健康受试者体内的药动学特征，并评价受试制剂和参比制剂在空腹和餐后给药时的生物等效性。方法 在健康成年受试者中采用随机、开放、两制剂、两序列、四周期、完全重复交叉试验设计。空腹和餐后分别入组健康成年受试者32例和36例，每周期单次给予受试制剂或参比制剂25 mg,清洗期14 d。采用高效液相色谱-串联质谱（HPLC-MS/MS）法测定人血浆中富马酸丙酚替诺福韦及其代谢物替诺福韦，并评估两种制剂的生物等效性。结果 平均生物等效性（ABE）评价标准，空腹试验中丙酚替诺福韦受试制剂与参比制剂AUC_0-t、AUC_0-∞几何均数比值90%置信区间分别为86.39%～103.42%,86.42%～103.42%;参比制剂标度的平均生物等效性（RSABE）评价标准，受试制剂与参比制剂峰浓度(C_max)的几何均值比约为88.39%,单侧95%置信区间上限为-0.010 4,符合高变异药物生物等效性要求；替诺福韦分别为87.73%～98.58%,91.44%～101.38%,92.57%～103.29%。餐后试验中丙酚替诺福韦受试制剂与参比制剂C_max、AUC_0-t、AUC_0-∞几何均数比值90%置信区间分别为82.98%～109.89%,91.17%～102.21%,91.46%～102.94%;替诺福韦分别为94.65%～103.19%,96.68%～103.73%,96.87%～104.11%。RSABE评价结果表明，餐后试验受试制剂与参比制剂C_max几何均值比值为95.49%,单侧95%置信区间上限为-0.201 0,符合高变异药物生物等效性要求。结论 空腹和餐后条件下单次口服富马酸丙酚替诺福韦受试制剂和参比制剂具有生物等效性。更多还原

【Abstract】 Objective To study the pharmacokinetic characteristics of tenofovir fumarate alafenamide and its metabolite tenofovir in healthy Chinese subjects and to evaluate the bioequivalence of test and branded preparation when administered under fasting and fed condition. Methods A randomized, open-label, two-preparation, two-sequence, four-period and fully replicated crossover bioequivalence trial was performed in healthy Chinese adult subjects.A total of 32 and 36 healthy subjects were enrolled in the fasting and fed trials, respectively.A single dose of test or reference tenofovir fumarate（25 mg） was administered under fasting or fed condition with a 14-day was hout period.The concentration of tenofovir fumarate and its metabolite tenofovir in human plasma was determined by high performance liquid chromatography-tandem mass spectrometry（HPLC-MS/MS）.Then, the bioequivalence of the two preparations was evaluated. Results Average-bioequivalence analysis demonstrated that 90% confidence intervals for the geometric mean ratio of AUC_0-t and AUC_0-∞of the tenofovir alafenamide in fasting condition were 86.39%-103.42% and 86.42%-103.42%,respectively.In addition, the point estimation for the geometric mean ratio of C_max was 88.39% and upper bound of 95% confidence interval was-0.010 4 by using the reference-scaled average bioequivalence（RSABE） method.On the other hand, 90% confidence intervals for geometric mean ratio of C_max,AUC_0-t and AUC_0-∞of tenofovir in fasting condition were 87.73%-98.58%,91.44%-101.38% and 92.57%-103.29%,respectively.Under fed conditions, 90% confidence intervals for geometric mean ratio of C_max,AUC_0-t and AUC_0-∞ between the test and reference preparation for tenofovir alafenamide were 82.98%-109.89%,91.17%-102.21% and 91.46%-102.94%,respectively.For tenofovir, these parameters were 94.65%-103.19%,96.68%-103.73% and 96.87%-104.11%,respectively.RSABE analysis demonstrated that the point estimation for the geometric mean ratio of C_max was 95.49% and the upper bound of 95% confidence interval was-0.201 0.All results also met the bioequivalence acceptance criteria. Conclusion This study demonstrated that 25 mg tenofovir fumarate test formulation is bioequivalent to the formulation marketed in healthy Chinese subjects under fasting and fed conditions.更多还原