Scheerans Christian, Derendorf Hartmut, Kloft Charlotte
Department of Clinical Pharmacy, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany.
Biopharm Drug Dispos. 2008 Apr;29(3):145-57. doi: 10.1002/bdd.596.
The area under the plasma concentration-time curve from time zero to infinity (AUC(0-inf)) is generally considered to be the most appropriate measure of total drug exposure for bioavailability/bioequivalence studies of orally administered drugs. However, the lack of a standardised method for identifying the mono-exponential terminal phase of the concentration-time curve causes variability for the estimated AUC(0-inf). The present investigation introduces a simple method, called the two times t(max) method (TTT method) to reliably identify the mono-exponential terminal phase in the case of oral administration. The new method was tested by Monte Carlo simulation in Excel and compared with the adjusted r squared algorithm (ARS algorithm) frequently used in pharmacokinetic software programs. Statistical diagnostics of three different scenarios, each with 10,000 hypothetical patients showed that the new method provided unbiased average AUC(0-inf) estimates for orally administered drugs with a monophasic concentration-time curve post maximum concentration. In addition, the TTT method generally provided more precise estimates for AUC(0-inf) compared with the ARS algorithm. It was concluded that the TTT method is a most reasonable tool to be used as a standardised method in pharmacokinetic analysis especially bioequivalence studies to reliably identify the mono-exponential terminal phase for orally administered drugs showing a monophasic concentration-time profile.
从零时间到无穷大的血浆浓度-时间曲线下面积（AUC(0-inf)）通常被认为是口服给药药物生物利用度/生物等效性研究中衡量药物总暴露量的最合适指标。然而，缺乏一种标准化方法来识别浓度-时间曲线的单指数终末相，导致估算的AUC(0-inf)存在变异性。本研究引入了一种简单的方法，称为两次t(max)法（TTT法），用于在口服给药情况下可靠地识别单指数终末相。该新方法在Excel中通过蒙特卡洛模拟进行了测试，并与药代动力学软件程序中常用的调整后r平方算法（ARS算法）进行了比较。对三种不同场景（每种场景有10000名虚拟患者）的统计诊断表明，对于最大浓度后呈单相浓度-时间曲线的口服给药药物，新方法提供了无偏的平均AUC(0-inf)估计值。此外，与ARS算法相比，TTT法通常为AUC(0-inf)提供更精确的估计值。得出的结论是，TTT法是一种非常合理的工具，可作为药代动力学分析尤其是生物等效性研究中的标准化方法，用于可靠地识别呈单相浓度-时间曲线的口服给药药物的单指数终末相。
