Shin Meong Cheol, Kim Jin-Ki, Kim Chong-Kook
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul Nationial University, Seoul, Korea.
Arzneimittelforschung. 2008;58(1):11-7. doi: 10.1055/s-0031-1296460.
The bioequivalence of a test formulation (Nanopril, "test") and a reference formulation ("reference") of lisinopril (CAS 83915-83-7) was demonstrated by in vivo and in vitro tests. The in vivo bioequivalence study in 26 healthy volunteers was designed as a single dose, randomized, double-blind trial with a 2-week washout period between the doses. Prior to the in vivo study, an in vitro comparative dissolution test was performed by the paddle method following the bioequivalence guidance of the Korea Food and Drug Administration (KFDA). By the results of the dissolution test it was demonstrated from the similar and rapidly dissolving patterns of the two lisinopril tablets that the two formulations were pharmaceutically equivalent. However, the in vivo bioequivalence study was required to fully evaluate the bioequivalence of the two drug products. In the in vivo bioequivalence study, the plasma samples drawn from the volunteers were analyzed utilizing a sensitive LC-MS-MS analysis method and the bioequivalence between the two drug products was assessed by statistical analysis of the log transformed mean ratios of Cmax,AUC(0-t) and AUC(0-infinity). The mean maximum concentration (Cmax) of the test and reference were found to be 60.41 +/- 20.07 ng/mL and 61.11 +/- 19.36 ng/mL, respectively. The 90% confidence intervals (C.I.) of Cmax were in the range from 0.91 to 1.08. As for the AUC(0-t) and the AUC(0-infinity), test values were 792.73 +/- 273.41 ng x mL(-1) x h, 862.74 +/- 303.81 ng x mL(-1) x h and the reference values were 841.66 +/- 286.07 ng . mL(-1) x h, 906.97 +/- 318.72 ng x mL(-1) x h, respectively. The 90% C. I. of AUC(0-t) were 0.86 to 1.01 and of AUC(0-infinity), 0.87 to 1.02 and thus were within the 80-125% interval proposed by the FDA. In addition to the 90% C.I. of the pharmaceutical parameters, a two-way ANOVA showed no significant difference between the two formulations. Based upon these statistical analyses, it was concluded that the test formulation is bioequivalent to the reference.
通过体内和体外试验证明了赖诺普利（CAS 83915-83-7）的受试制剂（纳米普利，“受试品”）与参比制剂（“参比品”）的生物等效性。在26名健康志愿者中进行的体内生物等效性研究设计为单剂量、随机、双盲试验，两次给药之间有2周的洗脱期。在进行体内研究之前，按照韩国食品药品管理局（KFDA）的生物等效性指导原则，采用桨法进行了体外比较溶出度试验。根据溶出度试验结果，两种赖诺普利片剂相似且快速溶解的模式表明这两种制剂在药学上是等效的。然而，需要进行体内生物等效性研究以全面评估这两种药品的生物等效性。在体内生物等效性研究中，利用灵敏的液相色谱-串联质谱分析方法对志愿者采集的血浆样本进行分析，并通过对Cmax、AUC(0-t)和AUC(0-∞)的对数转换平均比值进行统计分析来评估两种药品之间的生物等效性。受试品和参比品的平均最大浓度（Cmax）分别为60.41±20.07 ng/mL和61.11±19.36 ng/mL。Cmax的90%置信区间（C.I.）在0.91至1.08范围内。至于AUC(0-t)和AUC(0-∞)，受试品的值分别为792.73±273.41 ng·mL(-1)·h、862.74±303.81 ng·mL(-1)·h，参比品的值分别为841.66±286.07 ng·mL(-1)·h、906.97±318.72 ng·mL(-1)·h。AUC(0-t)的90% C.I.为0.86至1.01，AUC(0-∞)的90% C.I.为0.87至1.02，因此均在FDA提出的80 - 125%区间内。除了药学参数的90% C.I.外，双向方差分析显示两种制剂之间无显著差异。基于这些统计分析，得出受试制剂与参比制剂生物等效的结论。
