Elkoshi Z
Teva Pharmaceutical Industries Ltd., P.O. Box 353, Kfar-Sava 44102,
J Pharm Sci. 1999 Apr;88(4):434-44. doi: 10.1021/js980322p.
A procedure based on release rates is proposed for the establishment of dissolution specifications that ensure the bioequivalence of a test and a reference product. This procedure, which confines Cmax (the maximum concentration of the drug in vivo) and AUCinfinity (the area under the time-concentration curve, extrapolated to infinity) values within any desired range (relative to a reference product), can be used as an alternative to the methods presented in the FDA guidance1 or the USP.2 The method is appropriate for zero-order or first-order release products with linear Level A in vitro/in vivo correlations (IVIVC). Based on the result that the relative difference in Cmax must always be smaller than the relative difference in the absorption rate constants (for any test and reference products of a given drug), the "minimum range" specifications are set. These specifications, which are identical for both zero-order and first-order release products, are of general validity. They depend only on the relative extents of release, but are otherwise drug or formulation independent. For certain extended release products demonstrating a constant release rate that is unaffected by dissolution conditions (thus allowing the assumption of Level A IVIVC), the "minimum range" dissolution limits are applicable even when in vivo data is not available. If the reference product in vivo data is available, wider limits (which are product specific) may be set. If the drug disposition is monoexponential, the specifications generated are the widest possible. They are termed the "ideal" specifications. In the case of a multiexponential disposition, the limits set by the procedure will (generally) not be the widest possible. Although the method is based on one-compartment models, it is essentially model independent in the sense that microscopic modeling is redundant for its application.
本文提出了一种基于释放速率的方法，用于建立确保受试产品与参比产品生物等效性的溶出度标准。该方法可将Cmax（药物在体内的最大浓度）和AUCinfinity（时间-浓度曲线下的面积，外推至无穷大）值限制在任何所需范围内（相对于参比产品），可作为FDA指南1或USP.2中所述方法的替代方法。该方法适用于具有线性A级体外/体内相关性（IVIVC）的零级或一级释放产品。基于Cmax的相对差异必须始终小于吸收速率常数的相对差异这一结果（对于给定药物的任何受试产品和参比产品），设定了“最小范围”标准。这些标准对于零级和一级释放产品是相同的，具有普遍有效性。它们仅取决于相对释放程度，在其他方面与药物或制剂无关。对于某些显示恒定释放速率且不受溶出条件影响的缓释产品（因此可假定为A级IVIVC），即使没有体内数据，“最小范围”溶出限度也适用。如果有参比产品的体内数据，则可以设定更宽的限度（针对特定产品）。如果药物处置为单指数，则生成的标准是可能的最宽标准。它们被称为“理想”标准。在多指数处置的情况下，该方法设定的限度（通常）不是可能的最宽限度。尽管该方法基于单室模型，但从微观建模对其应用来说是多余的这一意义上讲，它本质上与模型无关。
