後発医薬品の生物学的同等性試験における先発医薬品と標準製剤 (先発医薬品) の薬物動態パラメータのバラツキに関する研究　～モンテルカストチュアブル錠を例として～

抄録

In clinical bioequivalence studies (BES) of generic products (GE), area under the curve (AUC) is the representative parameter for evaluating bioequivalence. The mean values of AUC are frequently different between original products (OP) and standard products (SP) used as references in BES for GE, and also different among SP. We investigated the differences in AUC between the OP of montelukast (Singulair^®) chewable tablet and each of the SP used in 25 BES of GE containing montelukast, and the differences in AUC among the SP. The ratios of AUC for SP to that for OP ranged from 1.15 to 1.69. The half-lives of OP, SP and intravenous administration were approximately 5.0 hours. The differences in AUC between OP and SP may be caused by racial differences in absorption because the half-lives are almost the same. The differences and distribution of AUC for SP relative to the data for OP were analyzed using a meta-analysis method. Standardized mean difference was 0.55 (95％ confidence interval: 0.33, 0.77). The AUC for SP were significantly larger than the minimum value in 11 of 13 BSE. On the other hand, absolute bioavailability (F) was 72.5 and 77.4％ for OP, and mean F (range) was 97.7 (77.9-113.9％) for SP, with a difference of approximately 20％ between OP and SP. From our results, better methods of assessment in BES should be proposed because of the large variation in AUC for SP.