吡罗昔康生物等效性研究中生物分析和临床部分的异常值数据来源。

Sandulovici Roxana, Mircioiu Ion, Aboul-Enein Hassan Y, Manolache Mihai, Mircioiu Constantin, Voicu Victor, Anuta Valentina

Int J Clin Pharmacol Ther. 2020 Nov;58(11):652-663. doi: 10.5414/CP203794.

OBJECTIVE

This paper analyzes the potential outliers in the bioanalytical and clinical part of a bioequivalence study, the effect on bioequivalence decisions whether or not it is appropriate to eliminate them from the statistical evaluation of bioequivalence.

MATERIALS AND METHODS

The clinical part was a cross-over, two periods, two sequences bioequivalence study concerning two piroxicam formulations, on healthy subjects. A simulation study evaluated the influence of 10% errors on the percent bias of calculated concentrations from nominal ones.

RESULTS

In bioequivalence studies, it is not possible to distinguish between relevant types of outliers based only on statistical criteria. The "problem" is particularly acute when the omission of outliers leads to a bias in the decision concerning bioequivalence from rejection to acceptance. In such cases, there is the suspicion of subjective analysis and torture of data. The effect of analytical errors at high plasma levels was criticized for the calculated concentrations in the neighborhood of lower limit of quantification. Errors at low concentrations have a less significant effect. In the pharmacokinetic analysis, several types of outliers were shown: single points, curves, pairs of curves corresponding to the same subject, intrasubject ratios of areas under curves and maximum concentrations. These pharmacokinetic outliers could have had, at the same time, bioanalytical, physiological and physicochemical causes.

CONCLUSION

Considering the results, it was proposed the following algorithm in the analysis of outlier data and outlier subjects in bioequivalence studies: evaluation of the implications of the decision concerning elimination of outliers on the decision concerning bioequivalence; application of the statistic tests for detection of outliers data; evaluations from the point of view of physiological pharmacokinetics, final decision concerning elimination of outliers.

目的

本文分析生物等效性研究的生物分析和临床部分中的潜在异常值，以及其对生物等效性判定的影响，即从生物等效性的统计评估中剔除这些异常值是否合适。

材料与方法

临床部分是一项关于两种吡罗昔康制剂的交叉、两期、两序列生物等效性研究，受试对象为健康受试者。一项模拟研究评估了10%的误差对计算浓度与标称浓度的百分比偏差的影响。

结果

在生物等效性研究中，仅基于统计标准无法区分相关类型的异常值。当剔除异常值导致生物等效性判定从拒绝变为接受出现偏差时，“问题”尤为严重。在这种情况下，存在主观分析和数据篡改的嫌疑。对于定量下限附近的计算浓度，高血浆水平下分析误差的影响受到批评。低浓度时的误差影响较小。在药代动力学分析中，显示出几种类型的异常值：单点、曲线、同一受试者对应的曲线对、曲线下面积和最大浓度的受试者内比值。这些药代动力学异常值可能同时具有生物分析、生理和物理化学原因。