富马酸替诺福韦二吡呋酯片的人体生物等效性

Bioequivalence of tenofovirdisoproxil fumarate tablets in Chinese healthy volunteers

目的:评价富马酸替诺福韦二吡呋酯片在健康人体空腹/餐后状态下生物等效性试验研究。方法:采用随机、开放、两周期、两交叉试验设计,26例男性健康受试者随机分成2组,分别空腹/餐后口服受试制剂或参比制剂300 mg,0~72 h间隔采集血样。以液相色谱串联质谱法(LC-MS/MS)法测定血浆替诺福韦浓度,用Win Nonlin软件计算药动学参数。结果:建立的LC-MS/MS法在1.00~600 ng·mL^(-1)范围内线性关系良好,最低定量限为1.00 ng·mL^(-1),批内及批间精密度(RSD)均小于15%。空腹口服受试和参比制剂后,血浆中替诺福韦的主要药动学参数如下:受试制剂和参比制剂的Tmax分别为(0.5±2)和(0.5±1.5)h,Cmax分别为(291.83±66.29)和(321.22±74.65)ng·mL^(-1),t1/2分别为(19.98±2.27)和(21.00±2.93)h,AUC0~72h分别为(2 404.73±532.72)和(2 522.65±567.08)h·ng·mL^(-1)。餐后口服受试和参比制剂后,受试制剂和参比制剂的Tmax分别为(0.75±5)和(1±8)h,Cmax分别为(261.31±101.27)和(292.22±122.67)ng·mL^(-1),t1/2分别为(19.38±2.39)和(19.44±2.26)h,AUC0~72h分别为(3 043.16±731.12)和(3 147.96±930.67)h·ng·mL^(-1)。结论:建立的LC-MS/MS法准确可靠,富马酸替诺福韦二吡呋酯片2种制剂具有人体生物等效性。

Objective： To investigate the bioequivalence of 2 formulations of tenofovirdisoproxil fumarate tablets in Chinese healthy volunteers under fasting and postprandial conditions. Methods： In a randomized two-way crossover study, 26 healthy male volunteers were divided into two groups and were administered with a single oral dose of test or reference formulations containing 300 mg tenofovirdisoproxil fumarate under fasting and postprandial conditions. The blood samples were collected at predetermined time intervals up to 72 h. The plasma concentration of tenofovir was determined by LC-MS/MS. The pharmacokinetic parameters were estimated by WinNonlin software. Results ： The established LC-MS/MS method had linear calibration range over 1.00 - 600 ng· mL^- 1 with a limit of quantitation （LLOQ） of 1.00 ng· mL^- 1 for tenofovir in human plasma. The intra- and inter-batch standard deviations were less than 15%. The pharmacokinetic parameters for the test and reference tablets under fasting conditions were as follows： T max（0.5 ±2） and （0.5 ±1.5） h, C （291.83 ±66.29） and （321.22 ±74.65） ng·mL^-1, t1/2（19.98 ±2.27） and （21.00±2.93） h, AUC0-72h（2404.73 ±532.72） and （2522.65±567.08） h·ng·mL^-1 The pharmacokinetie parameters for the test and reference tablets under postprandial conditions were as follows ： Tmax （0.75 ± 5 ） and （ 1 ± 8 ） h, Cmax （261.31 ± 101.27） and （292.22 ± 122.67） ng· mL^-1, t1/2 （19.38 ±2.39） and （19.44 ±2.26） h, AUC0-72h（3 043.16 ±731.12） and （3 147.96 ±930.67） h·ng·mL^-1, respectively. Conclusion： The method is suitable for the pharmaeokinetie study of tenofovirdisoproxil fumarate tablets, and the two preparations are bioequivalent.