Hauck W W, Parekh A, Lesko L J, Chen M L, Williams R L
Biostatistics Section, Division of Clinical Pharmacology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Int J Clin Pharmacol Ther. 2001 Aug;39(8):350-5. doi: 10.5414/cpp39350.
The US Food and Drug Administration (FDA) currently uses bioequivalence (BE) limits for fasting BE studies that are based on the 90% confidence interval for the ratio of difference of the test and reference products Cmax and AUC falling within 80% to 125%. The FDA has also proposed that BE limits be used similarly for AUC and Cmax measurements from fed BE studies. In some cases, regulatory agencies have considered a wider BE limit for Cmax, because of the typically higher variability of Cmax compared to AUC. We investigated the consequences of changing from an 80%/ 125% limit for both pharmacokinetic measures to one that uses a limit of 80%/125% for AUC and 70%/143% for Cmax.
We computed the sample sizes required for BE studies using 80%/125% for AUC and 70%/143% for Cmax as BE limits. We also determined the range of the ratios of Cmax and AUC values in a study that could meet the 70%/143% and 80%/125% BE limits.
The sample size for the study, in order to have adequate power with 80%/125% for AUC and 70%/143% for Cmax, will be determined primarily by the intrasubject variability of AUC, though with a substantial proportion of studies (about one third) still determined by the variability of Cmax. The ratio of mean Cmax values that can pass a wider 70%/143% BE limit could easily be as high as 128%.
Without further scientific or clinical rationale, we find it difficult to justify widening the bioequivalence limit for Cmax to 70%/143% for either fasting or fed BE studies.
美国食品药品监督管理局（FDA）目前在空腹生物等效性（BE）研究中使用的生物等效性限度是基于测试产品与参比产品的Cmax和AUC差值之比的90%置信区间落在80%至125%之间。FDA还提议将该生物等效性限度类似地用于进食BE研究中的AUC和Cmax测量。在某些情况下，监管机构考虑对Cmax采用更宽的生物等效性限度，因为与AUC相比，Cmax的变异性通常更高。我们研究了将两种药代动力学指标的80%/125%限度改为AUC采用80%/125%限度、Cmax采用70%/143%限度的后果。
我们计算了以AUC的80%/125%和Cmax的70%/143%作为生物等效性限度时BE研究所需的样本量。我们还确定了一项研究中能够满足70%/143%和80%/125%生物等效性限度的Cmax和AUC值之比的范围。
为了在AUC采用80%/125%、Cmax采用70%/143%时有足够的检验效能，该研究的样本量将主要由AUC的受试者内变异性决定，不过仍有相当比例（约三分之一）的研究由Cmax的变异性决定。能够通过更宽的70%/143%生物等效性限度的平均Cmax值之比很容易高达128%。
在没有进一步科学或临床依据的情况下，我们发现无论是空腹还是进食BE研究，将Cmax的生物等效性限度拓宽至70%/143%都难以自圆其说。
