Basson R P, Cerimele B J, DeSante K A, Howey D C
Lilly Laboratory for Clinical Research, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
Pharm Res. 1996 Feb;13(2):324-8. doi: 10.1023/a:1016019904520.
While peak drug concentration (Cmax) is recognized to be contaminated by the extent of absorption, it has long served as the indicator of change in absorption rate in bioequivalence studies. This concentration measure per se is a measure of extreme drug exposure, not absorption rate. This paper redirects attention to Tmax as the absorption rate variable.
We show that the time to peak measure (Tmax), if obtained from equally spaced sampling times during the suspected absorption phase, defines a count process which encapsulates the rate of absorption. Furthermore such count data appear to follow the single parameter Poisson distribution which characterizes the rate of many a discrete process, and which therefore supplies the proper theoretical basis to compare two or more formulations for differences in the rate of absorption. This paper urges limiting the use of peak height measures based on Cmax to evaluate only for dose-dumping, a legitimate safety concern with any formulation. These principles and techniques are illustrated by a bioequivalence study in which two test suspensions are compared to a reference formulation.
Appropriate statistical evaluation of absorption rate via Tmax supports bioequivalence, whereas the customary analysis with Cmax leads to rejection of bioequivalence. This suggests that the inappropriate use of Cmax as a surrogate metric for absorption rate contributes to the unpredictable and uncertain outcome in bioequivalence evaluation today.
虽然峰值药物浓度（Cmax）被认为受到吸收程度的影响，但长期以来它一直是生物等效性研究中吸收速率变化的指标。这种浓度测量本身是对极端药物暴露的测量，而非吸收速率。本文将关注点重新转向Tmax作为吸收速率变量。
我们表明，如果在疑似吸收阶段从等距采样时间获得达到峰值的时间测量值（Tmax），它定义了一个计数过程，该过程概括了吸收速率。此外，此类计数数据似乎遵循单参数泊松分布，该分布表征了许多离散过程的速率，因此为比较两种或更多制剂的吸收速率差异提供了适当的理论基础。本文敦促将基于Cmax的峰值高度测量的使用限制在仅评估剂量倾泻方面，这是任何制剂都合理关注的安全问题。通过一项生物等效性研究对这些原理和技术进行了说明，该研究将两种测试混悬液与一种参比制剂进行了比较。
通过Tmax对吸收速率进行适当的统计评估支持生物等效性，而使用Cmax进行的常规分析导致生物等效性被拒绝。这表明将Cmax不恰当地用作吸收速率的替代指标导致了当今生物等效性评估中不可预测和不确定的结果。
