Endrenyi L, Al-Shaikh P
Department of Pharmacology, University of Toronto, Ontario.
Pharm Res. 1995 Dec;12(12):1856-64. doi: 10.1023/a:1016267200905.
To develop a new method for the direct, sensitive evaluation of the equivalence of absorption rates in linear kinetic systems.
Concentrations are obtained before the earlier peak. Ratios of concentrations adjusted for the corresponding ratio of AUCs (area under the curve contrasting plasma concentration with time), or their logarithm, are extrapolated by linear regression to the time of drug administration. The intercept estimates the ratio of absorption rate constants (ka), or its logarithm.
The intercept metric assesses the equivalence of absorption rates with very favourable characteristics. The metric reflects the ka-ratio specifically (i.e., not affected by other kinetic parameters), is approximately linear to it, exhibits high kinetic sensitivity and excellent statistical properties. With many observations, the intercept metric has near-ideal features, including high power for determining bioequivalence and the ability to detect a 25% difference between ka values. With only 3 or 4 measurements before the earlier peak, the performance of the metric depends on the preset regulatory conditions. Reasonably good power is noted if the bioequivalence limits determine a 50% difference between two metrics and, approximately, between two ka values. The intercept metric shows very high power with a wider bioequivalence range. The power declines only moderately with increasing intraindividual variation of ka. The equivalence of absorption rates is assessed with much higher power by the intercept metric than by Cmax.
The excellent kinetic and statistical properties of the intercept metric enable the specific and sensitive determination of the equivalence of absorption rates.
开发一种用于直接、灵敏地评估线性动力学系统中吸收速率等效性的新方法。
在较早的峰之前获取浓度。根据相应的曲线下面积（AUC，即血浆浓度与时间对比曲线下的面积）比值调整后的浓度比值，或其对数，通过线性回归外推至给药时间。截距估计吸收速率常数（ka）的比值，或其对数。
截距指标评估吸收速率的等效性，具有非常良好的特性。该指标能特异性地反映ka比值（即不受其他动力学参数影响），与其大致呈线性关系，具有高动力学灵敏度和出色的统计学特性。在有许多观测值的情况下，截距指标具有近乎理想的特征，包括确定生物等效性的高功效以及检测ka值之间25%差异的能力。在较早的峰之前仅进行3或4次测量时，该指标的性能取决于预设的监管条件。如果生物等效性限度确定两个指标之间以及大致两个ka值之间存在50%的差异，则可观察到相当不错的功效。截距指标在更宽的生物等效性范围内显示出非常高的功效。随着ka个体内变异的增加，功效仅适度下降。与Cmax相比 使用截距指标评估吸收速率的等效性具有更高的功效。
截距指标出色的动力学和统计学特性能够特异性且灵敏地确定吸收速率的等效性。
