富马酸替诺福韦艾拉酚胺片人体生物等效性及饮食对其药动学的影响

Bioequivalence of Tenofovir Alafenamide Fumarate and Effects of Food on Its Pharmacokinetics

目的评价空腹和餐后单剂量口服两种富马酸替诺福韦艾拉酚胺片在健康中国人体中生物等效性,并考察饮食对替诺福韦艾拉酚胺体内药动学特征的影响。方法采用随机、开放、单剂量、两制剂、三序列、三周期、部分重复交叉生物等效性试验设计。空腹和餐后各入组42例健康受试者,每周期单次给予受试制剂或参比制剂25 mg,清洗期为10 d。用高效液相色谱-串联质谱(HPLC-MS/MS)法测定人血浆中替诺福韦艾拉酚胺及其代谢物替诺福韦的浓度,并评价两种制剂的生物等效性。结果空腹口服受试制剂与参比制剂后,替诺福韦艾拉酚胺的峰浓度(Cmax)分别为(268±103)、(272±134) ng·mL-1,血药浓度-时间曲线下面积(AUC0-120)分别为(146±51),(135±52)ng·h·mL-1,半衰期(t1/2)分别为(0.307±0.086)、(0.305±0.098)h,替诺福韦的Cmax分别为(9.94±3.16),(9.50±2.92)ng·mL-1,AUC0-120分别为(254±86),(239±72)ng·h·mL-1,t1/2分别为(39.9±6.7),(40.0±6.7)h。与空腹给药比较,餐后给药的替诺福韦艾拉酚胺AUC0-120增加77%,Cmax降低11%,峰时间(tmax)推迟1.2 h,替诺福韦tmax推迟1.6 h。结论两种制剂具有生物等效性,饮食对替诺福韦艾拉酚胺的药动学特征有明显影响。

Objective To investigate the bioequivalence of tenofovir alafenamide(TAF)fumarate under fasting and fed conditions and the food effect on the pharmacokinetics of TAF in healthy Chinese volunteers.Methods A randomized,open-label,single-dose,two-preparation,three-sequence,three-period,partial repeat cross-bioequivalence trial was performed in healthy Chinese volunteers.Both fasting and fed trials enrolled 42 healthy subjects.A single dose of test or reference tenofovir alafenamide fumarate tablet(25 mg)was administered under fasting or fed conditions per period with 10-day washout period.The concentrations of TAF and its metabolite tenofovir(TFV)in plasma were determined by HPLC-MS/MS.Results The pharmacokinetic parameters under fasting conditions for the test and reference tablets were as follows:for TAF,C max were(268±103)vs.(272±134)ng·mL-1,AUC 0-120 were(146±51)vs.(135±52)ng·h·mL-1,t 1/2 were(0.307±0.086)vs.(0.305±0.098)h;for TFV,C max were(9.94±3.16)vs.(9.50±2.92)ng·mL-1,AUC 0-120 were(254±86)vs.(239±72)ng·h·mL-1,t 1/2 were(39.9±6.7)vs.(40.0±6.7)h.For TAF,AUC 0-120 was 77%higher under fed versus fasting conditions,while C max was 11%lower.t max increased under fed compared with fasting conditions for both TAF and TFV.Conclusion The test and reference tablets are bioequivalent.Diet has a significant effect on the pharmacokinetics of TAF.