Kytariolos John, Karalis Vangelis, Macheras Panos, Symillides Mira
Laboratory of Biopharmaceutics-Pharmacokinetics, School of Pharmacy, University of Athens, Panepistimiopolis, Athens 15771, Greece.
Pharm Res. 2006 Nov;23(11):2657-64. doi: 10.1007/s11095-006-9107-1. Epub 2006 Oct 18.
(1) To develop novel scaled bioequivalence (BE) limits with levelling-off properties based solely on variability considerations and (2) to evaluate their performance in comparison to the classic unscaled BE limits 0.80-1.25, the expanded BE limits 0.75-1.33 and the recently proposed Geometric Mean Ratio (GMR)-dependent scaled BE limits BELscW (Karalis et al., Eur. J. Pharm. Sci., 26:54-61, 2005).
Two model functions were used to ensure the gradual change of the BE limits from a starting value towards a predefined plateau value. Plots of the new BE limits and extreme GMR values ensuring BE as a function of the coefficient of variation (CV) were constructed. Two-period crossover BE studies with 12, 24, or 36 subjects were simulated assuming CV values from 10 to 60%. Power curves were constructed by recording the percentage of accepted BE studies as the true GMR was raised from 1.00 to 1.50. The percentage of the true GMR within the simulated BE limits vs. true GMR was used to evaluate the estimation accuracy of the scaled methods.
Depending on the parameters' values of the model functions, the scaled BE limits exhibit different performance. Four new scaled BE limits, showing favourable performance for the evaluation of average BE are presented. At low variability levels two of the novel BE limits show similar performance to the 0.80-1.25 criterion, while the other two (as expected from their design) appear to be less permissive. At high CV values (30, 40%) all new BE limits exhibit much higher statistical power than the 0.80-1.25 criterion. They show almost identical behavior with the expanded 0.75-1.33 limits and appear to be less permissive than BELscW. Finally, the percentage of the true GMR within the simulated BE limits vs. true GMR shows a sharp decline. Due to the absence of the GMR factor in the model functions a more accurate estimation of the new scaled BE limits, compared to BELscW, is observed.
The new scaled BE limits appear to be highly effective at all levels of variation investigated and present satisfactory estimation accuracy.
（1）仅基于变异性考量开发具有平稳特性的新型标化生物等效性（BE）限度；（2）与经典的未标化BE限度0.80 - 1.25、扩展的BE限度0.75 - 1.33以及最近提出的基于几何平均比（GMR）的标化BE限度BELscW（Karalis等人，《欧洲药理学杂志》，26:54 - 61，2005年）相比较，评估它们的性能。
使用两个模型函数来确保BE限度从起始值逐渐变化至预定义的平稳值。构建了新的BE限度和确保生物等效性的极端GMR值随变异系数（CV）变化的图。假设CV值为10%至60%，模拟了12、24或36名受试者的两周期交叉BE研究。通过记录随着真实GMR从1.00提高到1.50时接受的BE研究的百分比来构建功效曲线。使用模拟的BE限度内真实GMR的百分比与真实GMR的关系来评估标化方法的估计准确性。
根据模型函数的参数值，标化的BE限度表现出不同的性能。给出了四个新的标化BE限度，它们在评估平均生物等效性方面表现出良好的性能。在低变异水平下，两个新的BE限度与0.80 - 1.25标准表现出相似的性能，而另外两个（从其设计预期）似乎更为严格。在高CV值（30%、40%）时，所有新的BE限度都表现出比0.80 - 1.25标准高得多的统计功效。它们与扩展的0.75 - 1.33限度表现出几乎相同的行为，并且似乎比BELscW更为严格。最后，模拟的BE限度内真实GMR的百分比与真实GMR的关系显示出急剧下降。由于模型函数中没有GMR因子，与BELscW相比，观察到新的标化BE限度的估计更为准确。
新的标化BE限度在所有研究的变异水平上似乎都非常有效，并且具有令人满意的估计准确性。
