Karalis Vangelis, Macheras Panos, Symillides Mira
Laboratory of Biopharmaceutics-Pharmacokinetics, School of Pharmacy, University of Athens, Panepistimiopolis, Athens 157 71, Greece.
Eur J Pharm Sci. 2005 Sep;26(1):54-61. doi: 10.1016/j.ejps.2005.04.019.
In this study, novel approaches for the design of bioequivalence (BE) limits are developed. The new BE limits scale with intrasubject variability but only until a geometric mean ratio (GMR)-dependent plateau value and combine the classic (0.80-1.25) and expanded (0.70-1.43) BE limits into a single criterion. Plots of the extreme GMR values accepted as a function of coefficient of variation (CV) have a convex shape, similar to the classic unscaled 0.80-1.25 limits. The performance of the novel approaches in comparison to the classic unscaled 0.80-1.25 limits as well as the two expanded BE limits, i.e., 0.70-1.43 and 0.75-1.33 was assessed using simulated data. Two-period crossover BE investigations with 12, 24 or 36 subjects were simulated with assumptions of CV 10%, 20%, 30% or 40%. At low CV values, the performance of the novel BE limits is almost identical to the 0.80-1.25 criterion. On the contrary, the expanded BE limits are very permissive even at high GMR values. For high CV% values (30% and 40%), the new BE limits show a much greater probability of declaring BE when GMR = 1 in comparison to the classic 0.80-1.25 limits. In addition, when the drug products differ more than 25%, the new BE limits show much lower percentage of acceptance than the expanded 0.70-1.43 limits. One of the major advantages of the new BE limits is their gradual expansion with variability until a GMR-dependent plateau value. Finally, the continuity and leveling-off properties of the new BE limits make them suitable for the assessment of BE studies, irrespective of the level of variability encountered.
在本研究中，开发了生物等效性（BE）限度设计的新方法。新的BE限度随个体内变异性而变化，但仅到一个依赖几何平均比（GMR）的平稳值，并将经典的（0.80 - 1.25）和扩展的（0.70 - 1.43）BE限度合并为一个单一标准。作为变异系数（CV）函数接受的极端GMR值的图呈凸形，类似于经典的未缩放的0.80 - 1.25限度。使用模拟数据评估了新方法与经典的未缩放的0.80 - 1.25限度以及两个扩展的BE限度（即0.70 - 1.43和0.75 - 1.33）相比的性能。模拟了具有12、24或36名受试者的两周期交叉BE研究，假设CV为10%、20%、30%或40%。在低CV值时，新BE限度的性能几乎与0.80 - 1.25标准相同。相反，即使在高GMR值时，扩展的BE限度也非常宽松。对于高CV%值（30%和40%），与经典的0.80 - 1.25限度相比，当GMR = 1时，新BE限度显示出宣布生物等效的可能性要大得多。此外，当药品差异超过25%时，新BE限度的接受百分比比扩展的0.70 - 1.43限度低得多。新BE限度的主要优点之一是它们随变异性逐渐扩展，直到一个依赖GMR的平稳值。最后，新BE限度的连续性和平稳特性使其适用于BE研究的评估，而不论遇到的变异性水平如何。
