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生物等效性研究  

Bioequivalence Study of Tenofovir Fumarate and Its Metabolite Tenofovir in Chinese Healthy Subjects

作　　者：陈红 邱雯[2] 吉兴芳 王志鹏 骆平英 刘海艳 CHEN Hong;QIU Wen;JI Xingfang;WANG Zhipeng;LUO Pingying;LIU Haiyan(Department of Integrated Traditional Chinese and Western Medicine,the Second Affiliated Hospital of Chengdu Medical College,China National Nuclear Corporation 416 Hospital,Chengdu 610057,China;National Drug Clinical Trial Institution,the Second Hospital,Lanzhou University Lanzhou 730030,China;School of Pharmacy,Lanzhou University,Lanzhou 730030,China;Hunan Creates Pharmaceutical Technology Co.,Changsha 410205,China)

机构地区：[1]成都医学院第二附属医院·核工业四一六医院中西医结合科,成都610057 [2]兰州大学第二医院国家药物临床试验机构,兰州730030 [3]兰州大学药学院,兰州730030 [4]湖南科锐斯医药科技有限公司,长沙410205

出　　处：《医药导报》2023年第6期789-796,共8页Herald of Medicine

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-0.0104,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-0.2010,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。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-0.0104 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-0.2010.All results als

关 键 词：富马酸丙酚替诺福韦 替诺福韦 生物等效性 药动学 高效液相色谱-串联质谱法 

分 类 号：R978.7[医药卫生—药品] R969.1[医药卫生—药学] R512.6