College of Pharmacy, Chungnam National University, Daejeon 305-764, South Korea.
Eur J Pharm Sci. 2010 Jan 31;39(1-3):175-80. doi: 10.1016/j.ejps.2009.11.013. Epub 2009 Dec 2.
Several strategies for overcoming the challenge of establishing bioequivalence (BE) for highly variable drugs (HVDs; drugs having within-subject variability >0.3) have been considered in recent years. Within-subject variability of the area under the curve (AUC(4h)) and peak concentration (C(max)) of doxifluridine in the minimal group (n=24) were 0.444 and 0.491, respectively, meeting the criteria for an HVD. For the large group (n=60), within-subject variability of the AUC(4h) and C(max) were 0.431 and 0.493, respectively. The 90% confidence interval for the AUC(4h) and C(max) of the ratio of the test drug to the reference drug exceeded the acceptable BE limits (0.80-1.25) of the ABE (average bioequivalence), in both the minimal and large groups. However, the 90% CI fell within the extended BE limits (0.61-1.64) of the SABE (scaled average bioequivalence), calculated using within-subject variability. The 95% CI of the AUC(4h) and C(max) of the ratio of test to reference drug were within the extended BE limit (<1.73) of the PBE (population bioequivalence), calculated using total variance. Our results suggest that the SABE method may be useful for evaluating the BE of HVDs and for meeting the need for international guidelines for BE.
近年来，人们已经考虑了几种克服高变异药物（HVD；个体内变异性>0.3 的药物）生物等效性（BE）建立挑战的策略。在最小组（n=24）中，多西氟尿苷的曲线下面积（AUC(4h)）和峰浓度（C(max)）的个体内变异性分别为 0.444 和 0.491，符合 HVD 的标准。对于大组（n=60），AUC(4h)和 C(max)的个体内变异性分别为 0.431 和 0.493。试验药物与参比药物比值的 AUC(4h)和 C(max)的 90%置信区间超过了 ABE（平均生物等效性）可接受的 BE 限度（0.80-1.25），在最小组和大组中均如此。然而，90%CI 在 SABE（比例平均生物等效性）的扩展 BE 限度（0.61-1.64）内，这是使用个体内变异性计算得出的。试验药物与参比药物比值的 AUC(4h)和 C(max)的 95%CI 在 PBE（群体生物等效性）的扩展 BE 限度（<1.73）内，这是使用总方差计算得出的。我们的结果表明，SABE 方法可能有助于评估 HVD 的 BE，并满足 BE 国际指南的需求。
