Thway Theingi M, Macaraeg Chris R, Calamba Dominador, Brunner Laura A, Eschenberg Michael, Pourvasei Ramak, Zhang Liana, Ma Mark, Desilva Binodh
Department of Pharmacokinetics & Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.
Bioanalysis. 2010 Sep;2(9):1587-96. doi: 10.4155/bio.10.75.
Incurred sample reanalysis (ISR) is the most recent in-study validation parameter that regulatory agencies have mandated to ensure reproducibility of bioanalytical methods supporting pharmacokinetic/toxicokinetic and clinical studies. The present analysis describes five representative case studies for macromolecule therapeutics.
Single ISR acceptance criteria (within 30% of the averaged or original concentration) and a modified Bland-Altman (BA) approach were used to assess accuracy and precision of ISR results. General concordance between the two criteria was examined using simulation studies.
All five methods met the ISR criteria. The results indicated that thorough method development and prestudy validation were prerequisites for a successful ISR. The overall agreement between the original and reanalyzed results as determined by BA was within 20%. Simulation studies indicated that concordance between the ISR criteria and BA was observed in 95% of the cases. Dilution factors had no significant impact on the ISR, even for C(max) samples where 1:100 or higher dilutions were used.
The current ISR acceptance criteria for macromolecules was scientifically and statistically meaningful for methods with a total error of 25% or less.
已产生样本再分析（ISR）是监管机构强制要求的最新研究内验证参数，以确保支持药代动力学/毒代动力学及临床研究的生物分析方法具有可重复性。本分析描述了大分子治疗药物的五个代表性案例研究。
采用单一ISR验收标准（在平均浓度或原始浓度的30%以内）和改良的布兰德-奥特曼（BA）方法来评估ISR结果的准确性和精密度。使用模拟研究检查了这两个标准之间的总体一致性。
所有五种方法均符合ISR标准。结果表明，全面的方法开发和研究前验证是成功进行ISR的先决条件。由BA确定的原始结果与再分析结果之间的总体一致性在20%以内。模拟研究表明，在95%的案例中观察到ISR标准与BA之间的一致性。稀释因子对ISR没有显著影响，即使对于使用1:100或更高稀释度的C(max)样本也是如此。
当前大分子的ISR验收标准对于总误差为25%或更低的方法在科学和统计上具有意义。
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