Midha K K, Rawson M J, Hubbard J W
Drug Metabolism, Drug Disposition Research Group, College of Pharmacy and Nutrition, Saskatoon, SK, S7N 5C9, Canada.
Eur J Pharm Sci. 1998 Apr;6(2):87-91. doi: 10.1016/s0928-0987(97)00080-8.
This study demonstrated that the mere fact that two multisource drug formulations are bioequivalent with the same reference formulation does not guarantee that they are bioequivalent with each other. The present unscaled bioequivalence limits (BEL) of 0.80 to 1.25 permitted far greater deviation from unity of the geometric mean ratio (GMR) for multisource formulations with low within-subject variabilities than for drugs with high variabilities. Scaling the BEL drastically reduced the maximum deviation from unity of GMRs for two multisource formulations each bioequivalent with the same reference product while broadening the BEL for highly variable drugs. It was concluded that scaling was consistent with the principle of switchability for toxic drugs with low variability and for safe, highly variable drugs. On the other hand, scaling need not be applied to safe drugs with low variability and should not be applied in the unusual case of a highly variable drug with a narrow therapeutic range.
本研究表明，两种多源药物制剂与同一参比制剂生物等效这一事实本身，并不能保证它们彼此之间也生物等效。目前未进行标化的生物等效性限度（BEL）为0.80至1.25，与高变异性药物相比，对于体内变异性低的多源制剂，几何平均比值（GMR）偏离1的允许偏差要大得多。对标化BEL极大地降低了两种与同一参比产品生物等效的多源制剂GMR偏离1的最大偏差，同时拓宽了高变异性药物的BEL。得出的结论是，标化符合低变异性毒性药物以及安全的高变异性药物的可替换性原则。另一方面，标化不适用于低变异性的安全药物，在治疗窗窄的高变异性药物这种特殊情况下也不应应用。
