Endrenyi L, Csizmadia F, Tothfalusi L, Chen M L
Department of Pharmacology, University of Toronto, Ontario, Canada.
Pharm Res. 1998 Aug;15(8):1292-9. doi: 10.1023/a:1011912512966.
To compare the effectiveness of various metrics which evaluate bioequivalence in the early phase of concentration-time profiles.
Two-period crossover trials were simulated with increasing assumed ratio of the true absorption rate constants of the two formulations, and with various kinetic models. Kinetic sensitivities (KS) and standard errors (SE) of the various metrics were recorded and the percentage of trials accepting bioequivalence (the statistical power) was evaluated. The principal metrics included the partial AUC(AUCP), the intercept obtained by linear extrapolation of the ratios of the lower over higher concentrations (C) measured for the two formulations (I L/H), and the ratios of intercepts extrapolated from logarithmic C/ time values of the two products (MLOG). For comparison, also properties of CMAX and an ideally evaluated measure (Id) were determined.
MLOG showed generally the highest statistical power and KS, and also the largest SE, closely followed by I L/H. Partial AUC exhibited lower power and KS, but also smaller SE than the intercept procedures. The three methods had much higher power, KS and SE than CMAX. These comparisons were maintained over various kinetic conditions and experimental designs. The effective evaluation of bioequivalence in the early phase of studies is assured with 3 (or more) measurements until the population average peak of the reference formulation.
The three principal methods assess bioequivalence very effectively in the early phase of a concentration-time profile. MLOG had the highest statistical power, closely followed by I L/H and then by partial AUC.
比较在浓度-时间曲线早期阶段评估生物等效性的各种指标的有效性。
采用两周期交叉试验进行模拟，增加两种制剂真实吸收速率常数的假定比值，并采用各种动力学模型。记录各种指标的动力学敏感性（KS）和标准误差（SE），并评估接受生物等效性的试验百分比（统计效能）。主要指标包括部分AUC（AUCP）、通过对两种制剂测量的较低浓度与较高浓度之比（C）进行线性外推得到的截距（I L/H），以及从两种产品的对数C/时间值外推得到的截距之比（MLOG）。为作比较，还测定了CMAX和理想评估指标（Id）的性质。
一般而言，MLOG显示出最高的统计效能和KS，其SE也最大，紧随其后的是I L/H。部分AUC的效能和KS较低，但其SE也小于截距法。这三种方法的效能、KS和SE均远高于CMAX。在各种动力学条件和实验设计中，这些比较结果均保持一致。在研究早期阶段，在获得参比制剂的群体平均峰之前进行3次（或更多次）测量，可确保有效评估生物等效性。
这三种主要方法在浓度-时间曲线早期阶段能非常有效地评估生物等效性。MLOG的统计效能最高，紧随其后的是I L/H，然后是部分AUC。
