Laboratory of Biopharmaceutics-Pharmacokinetics, School of Pharmacy, University of Athens, Athens, Greece.
Eur J Pharm Sci. 2011 Nov 20;44(4):497-505. doi: 10.1016/j.ejps.2011.09.008. Epub 2011 Sep 16.
Recently, the European Medicines Agency (EMA) issued a new guideline on the investigation of bioequivalence (BE). In case of highly variable drugs, this guideline proposes that the acceptance limits for C(max) can gradually be expanded as a function of within-subject variability (CV(wR)). Actually, these BE limits exhibit leveling-off properties since they are not allowed to scale continuously, but only up to CV(wR)=50%. To avoid the risk of accepting two drug products which may differ significantly, this EMA guideline also proposes the use of a secondary constraint criterion on the geometric mean ratio (GMR) of the two products under comparison. Aim of this study was to explore the leveling-off properties of the new EMA limits in comparison to other approaches, as well as to assess the impact of the complementary GMR criterion on the ability to declare bioequivalence. Simulated bioequivalence studies and extreme GMR plots were used to assess the performance of the EMA limits. Three sequence, three period (3×3) crossover studies with two treatments (T and R) were simulated. The R product was considered to be administered twice, while the T only once (i.e., TRR/RTR/RRT). Among others, this study revealed the leveling-off properties of the new EMA limits. It was also shown that the complementary GMR-constraint is only effective when a large sample size is used and at regions of CV(wR) close to 50%. This GMR-criterion begins to be effective at sample sizes around 60 and becomes more prominent as the number of subjects participating in the BE study increases. For CV(wR) values lower than 50%, the GMR-constraint has no role. In case of within-subject variabilities greater than 50%, the impact of the GMR-constraint diminishes due to the leveling-off properties of the EMA limits. Compared to the classic 0.80-1.25 or the extended 0.75-1.33 criteria, the new EMA limits are more liberal at high CV(wR) values and allow greater differences between the two drug products to be declared bioequivalent. Finally, this study showed that the use of an approximate value (0.760) on the scaling factor proposed by EMA, has no impact on the performance of the new BE limits compared to other more accurate approaches.
最近，欧洲药品管理局（EMA）发布了一项关于生物等效性（BE）研究的新指南。对于变异性高的药物，该指南建议可以根据个体内变异性（CV（WR））逐渐扩大 C（max）的接受限度。实际上，这些 BE 限度具有平稳化特性，因为它们不允许连续缩放，只能扩展到 CV（WR）=50%。为了避免接受可能存在显著差异的两种药物产品的风险，EMA 指南还建议在比较的两种产品的几何平均比（GMR）上使用次要约束标准。本研究旨在探讨新 EMA 限度与其他方法相比的平稳化特性，并评估补充 GMR 标准对宣布生物等效性的能力的影响。使用模拟生物等效性研究和极端 GMR 图来评估 EMA 限度的性能。使用三种序列、三种周期（3×3）交叉研究和两种处理（T 和 R）进行模拟。R 产品被认为是两次给药，而 T 产品仅一次给药（即 TRR/RTR/RRT）。除其他外，本研究揭示了新 EMA 限度的平稳化特性。还表明，当使用较大的样本量和接近 CV（WR）50%的区域时，补充 GMR-约束才有效。该 GMR 标准在大约 60 个样本量左右开始有效，并随着参与 BE 研究的受试者数量的增加而变得更加显著。对于低于 CV（WR）50%的值，GMR 标准没有作用。在个体内变异性大于 50%的情况下，由于 EMA 限度的平稳化特性，GMR 标准的影响会减弱。与经典的 0.80-1.25 或扩展的 0.75-1.33 标准相比，新的 EMA 限度在高 CV（WR）值下更为宽松，并允许在两种药物产品之间宣布更大的差异为生物等效。最后，本研究表明，与其他更准确的方法相比，使用 EMA 提出的缩放因子的近似值（0.760）对新 BE 限度的性能没有影响。
