两种国产抗结核固定剂量复合剂中利福平的药代动力学和生物等效性研究

Study on Pharmacokinetics and Bioequivalence of Rifampicin in Fixed-dose Combination

目的研究两种国产抗结核固定剂量复合剂四药复方中利福平的药代动力学和相对生物利用度，评价复合剂中利福平的生物等效性，以期揭示抗结核固定剂量复合剂的内在质量，为临床合理用药提供理论依据。方法复合剂作为受试制剂，利福平胶囊作为参比制剂，采用单次给药自身交叉对照的方法，考察两种受试制剂分两批试验进行，按照编号法将每批18名健康男性受试者随机分为2组．每组9名，第一批试验中组1受试者在第一周口服受试制剂l，每批试验入组18名受试者，两批试验共计入组36名受试者。第二周口服参比制剂，组2受试者在第一周口服参比制剂，第二周口服受试制剂1，每名受试者每周各服一次药物；第二批试验中受试制剂l改为受试制剂2，其他操作不变。服药后，抽取不同时间点受试者的静脉血，采用液相色谱一质谱联用法测定血药浓度，应用DAS3．1．5版软件计算药代动力学参数及判断生物等效性。结果两种固定剂量复合剂中利福平主要药代动力学参数分别如下，峰浓度（Cmax为（11．4±3．4）mg／L和（12．2±3．8）mg／L，半衰期（T1/2）为（3．7±1．2）h和（3．6±1．3）h，时间点0至24h的血药浓度一时间曲线下面积（AUC（0-t）为（91．4±30．8）mg·L^-1·h^-1和（92．1±25．3）mg·L^-1·h^-1，时间点0至无穷大时血药浓度一时间曲线下面积（AUC（n-∞）为（93.3±31．3）mg·L^-1·h^-1和（94．1±26．5）mg·L^-1·h^-1。AUC（0-t）相对生物利用度分别为94．7％和91．4％，置信区间为89．5％～100．2％和81．4％~95．6％，等效区间为80％~125％。结论两种受试制剂中利福平的Cmax、Tmax与参比制剂比较均无显著性差异。经生物等效性检验，判定两种受试制剂中利福平与参比制剂中利福平生物等效。

Objective To study the pharmacokinetics and relative bioavailability and to assess the bioequiva lence of compound rifampicin in two kinds of fixed-dose combination （FDC） formulations containing four anti-tuberculosis agents for ensuring its quality of FDC formulations for rational drug use. Methods The randomized, crossover study was conducted in 18 healthy male volunteers for each FDC; formulation （FDC; 1 for studyl and FDC2 for study2）.Totally, 36 individuals were enrolled in these 2 studies.There were 2 groups for each study, every 9 volunteers for each group. Using FDC formulation for tested preparation and separated formulation （rifampicin capsules） as reference preparation, a single oral dose of two preparations（reference preparation and FDC;） was given to 2 groups＇ volunteers respectively. The rifampicin concentrations in plasma of volunteers were determined by LC-MS/MS. The pharmacokinetic parameters and relative bioavailability were calculated by DAS 3.1.5 software and the bioequivalenee of each FDC fomulation was evaluated. Results The major pharmacokinetics parameters of compound rifampicin of two FDC formulations were showed respectively. For FDC 1 and FDC2, Cm~ were （11.4 ± 3.4） mgoLl and （12.2 ± 3.8） mg·L,T1/2 were （3.7 ± 1.2） h and （3.6 ± 1.3） h, AUC（0-t） were （91.4± 30.8） mg·L^-1·h^-1 and （92.1 ± 25.3） mg·L^-1·h^-1,AUC（0-∞） were （93.3±31.3） mg·L^-1·h^-1 and （94.1 ±26.5） mg·L^-1·h^-1.The relative bioavailability of AUC〈0.t）was 94.7% （CI=89.5%--100.2%）, 91.4% （C1=81.4%--95.6%）, respectively. Conclusion The pharmacokinetics parameters shows that these two FDC formulations are both bioequivalent for rifampicin to the reference preparation.There is no significant difference for C~, T~ between these two kinds of FDC formulations and the reference preparation.