Endrenyi L, Tothfalusi L
Department of Pharmacology, University of Toronto, Ontario.
Int J Clin Pharmacol Ther. 1997 Apr;35(4):142-50.
Crossover trials were simulated in order to evaluate whether shortening the duration of bioequivalence trials for drugs with long half-lives would adversely affect the statistical properties of estimated AUC ratios. The trials were simulated under a wide range of assumed kinetic and experimental conditions. The duration of the simulated experiments was gradually shortened and ratios of truncated AUCs were evaluated. In addition, simulations by Martinez and Jackson [1991] were substantially extended. It was demonstrated that the variation of truncated AUCs did not rise, and their bias was negligible when investigations were limited to 2 (and under many conditions to 1) half-lives following drug administration. With large variability of clearance, high limit of quantitation, and/or 2-compartmental models, the observed variation actually often increased when the duration of a study was extended. It was concluded that the assessment of bioequivalence for long half-life drugs would not be adversely affected by limiting the duration of an investigation and, consequently, by using truncated AUCs.
为了评估缩短长半衰期药物生物等效性试验的持续时间是否会对估计的AUC比值的统计特性产生不利影响，进行了交叉试验模拟。这些试验在广泛的假定动力学和实验条件下进行模拟。模拟实验的持续时间逐渐缩短，并对截断AUC的比值进行评估。此外，Martinez和Jackson [1991]的模拟得到了大幅扩展。结果表明，当研究限于给药后2个（在许多情况下为1个）半衰期时，截断AUC的变异性没有增加，其偏差可以忽略不计。在清除率变异性大、定量上限高和/或二室模型的情况下，当研究持续时间延长时，观察到的变异性实际上常常增加。得出的结论是，限制研究持续时间并因此使用截断AUC，不会对长半衰期药物的生物等效性评估产生不利影响。
