拉米夫定替诺福韦片在中国健康受试者体内的生物等效性研究

Bioequivalence of lamivudine tenofovir tablets in Chinese healthy subjects

目的 评价拉米夫定替诺福韦片在中国健康受试者体内的药代动力学和生物等效性。方法 采用随机、开放、单剂量、两周期、双交叉给药试验设计。空腹及餐后试验各入组24例健康受试者,随机分为2组,每周期单次空腹或餐后口服受试制剂1片或2种参比制剂各1片。用HPLC-MS/MS法测定给药后不同时间点拉米夫定和替诺福韦的血药浓度。用WinNonlin7.0软件按非房室模型计算药代动力学参数,并进行生物等效性评价。结果 受试者空腹口服受试制剂和参比制剂后的药代动力学参数:拉米夫定C_(max)分别为(2 777.74±702.55)和(2 985.00±979.23) ng·mL^(-1),AUC_(0-t)分别为(11 977.14±2 550.67)和(12 450.22±2 336.41)ng·h·mL^(-1),AUC_(0-∞)分别为(12 177.69±2 526.02)和(12 660.98±2 333.30)ng·h·mL^(-1);替诺福韦C_(max)分别为(316.72±63.79)和(301.46±79.82) ng·mL^(-1),AUC_(0-t)分别为(2 584.72±619.04)和(2 474.94±636.05)ng·h·mL^(-1),AUC_(0-∞)分别为(2 789.87±701.97)和(2 666.35±676.21)ng·h·mL^(-1)。受试者餐后口服受试制剂和参比制剂后的药代动力学参数:拉米夫定C_(max)分别为(2 079.46±583.92)和(2 084.28±517.59) ng·mL^(-1),AUC_(0-t)分别为(10 628.86±1 751.63)和(10 573.70±2 059.54)ng·h·mL^(-1),AUC_(0-∞)分别为(10 827.86±1 734.39)和(10 791.93±2 098.91)ng·h·mL^(-1);替诺福韦C_(max)分别为(286.97±85.91)和(271.79±63.64) ng·mL^(-1),AUC_(0-t)分别为(3 087.01±707.76)和(3 023.48±612.46)ng·h·mL^(-1),AUC_(0-∞)分别为(3 307.08±746.76)和(3 221.56±672.44)ng·h·mL^(-1)。C_(max)、AUC_(0-t)、AUC_(0-∞)的几何均数比值(受试制剂/参比制剂)的90%置信区间统计结果均在80.00%~125.00%等效范围内。结论 受试制剂拉米夫定替诺福韦片与参比制剂拉米夫定片和富马酸替诺福韦二吡呋酯片在空腹和餐后给药条件下具有生物等效性。

Objective To evaluate the bioequivalence of lamivudine tenofovir tablets in Chinese healthy volunteers.Methods A randomized,open,single-dose,two-period,double-crossover drug trial design was conducted.24 subjects were randomly divided into two groups,and administered orally one tablet of test preparation or one tablet of each reference preparation per period under fasting and fed condition respectively.The concentrations of lamivudine and tenofovir in plasma were determined by HPLC-MS/MS.The pharmacokinetic parameters were calculated and the bioequivalence was compared by non-compartment model of WinNonlin 7.0 program.Results The pharmacokinetic parameters of test and reference preparations after fasting oral administration:lamivudine C_(max) were(2 777.74±702.55) and(2 985.00±979.23)ng·mL^(-1),AUC_(0-t) were(11 977.14±2 550.67) and(12 450.22±2 336.41) ng·h·mL^(-1),AUC_(0-∞) were(12 177.69±2 526.02) and(12 660.98±2 333.30) ng·h·mL^(-1),respectively;tenofovir C_(max) were(316.72±63.79)and(301.46±79.82) ng·mL^(-1),AUC_(0-t) were(2 584.72±619.04) and(2 474.94±636.05) ng · h·mL^(-1),AUC_(0-∞) were(2 789.87±701.97) and(2 666.35±676.21) ng · h·mL^(-1),respectively.The pharmacokinetic parameters of test and reference preparations after fed oral administration:lamivudine C_(max) were(2 079.46±583.92)and(2 084.28±517.59) ng · mL^(-1),AUC_(0-t) were(10 628.86±1 751.63) and(10 573.70±2 059.54)ng·h·mL^(-1),AUC_(0-∞) were(10 827.86±1 734.39) and(10 791.93±2 098.91) ng · h·mL^(-1),respectively;tenofovir C_(max) were(286.97±85.91) and(271.79±63.64) ng · mL^(-1),AUC_(0-t) were(3 087.01±707.76) and(3 023.48±612.46) ng·h·mL^(-1),AUC_(0-∞) were(3 307.08±746.76) and(3 221.56±672.44) ng · h·mL^(-1),respectively.The statistical results of the 90% confidence intervals of the geometric mean ratios of C_(max),AUC_(0-t) and AUC_(0-∞)(test preparation/reference preparation) were all within the equivalent range of 80.00%-125.00%.Conclusion The test and reference preparations of lamivudine tenofovir tablets were bioequivalent in healthy Chinese subjects under fasting and fed conditions.