The impact of stereoisomerism in bioequivalence studies.
The impact of stereoisomerism in bioequivalence studies.
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DOI：
10.1021/js9703683
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发表时间：
1998-07
影响因子：
3.8
通讯作者：
K. Midha;G. Mckay;M. Rawson;J. Hubbard
中科院分区：
文献类型：
--
作者：
K. Midha;G. Mckay;M. Rawson;J. Hubbard
立体异构体在药代动力学、药效学和毒理学研究中的重要性现已得到充分证实，并已成为几篇综述文章的主题。然而，立体异构体在生物等效性(BE)研究中的影响仍然是一个有争议的问题。13-21那些赞成在BE研究中使用立体选择性方法的人倾向于建立在理论药代动力学、药效学或毒理学基础上，以及现在可用于许多手性药物的立体选择性分析方法的事实上。那些反对在所有BE研究中使用立体选择方法的人指出，立体选择分析方法不一定简单，而且，传统的BE研究基于交叉设计，其中异构体的混合物以相同的比例给予所有受试者，在给予测试和参考配方后，在相同的条件下比较最大暴露(Cmax)和暴露程度(AUC)。卡里姆16对瑞典一个监管机构1991年提出的关于使用立体选择性分析评估外消旋药物的BE的第一批建议，以及1992年举行的“分析方法验证：生物利用度、BE和药代动力学研究”会议20提出的建议进行了批判性评价。目前北美、欧洲和日本对立体异构体药物的监管指南是Laganiere最近一项全面审查的主题。22然而，世界各地不同的管理机构之间仍然存在相当大的差距，关于在BE研究中使用立体选择方法的国际协调概念仍然是未来需要实现的一个重要目标。国际辩论的一个合乎逻辑的起点可能是一个合理的算法，16用于决定是否应使用立体选择性方法来评估外消旋药物的两种剂型的BE。根据该算法(图1)，立体选择性方法应在两种情况下使用：(I)当产生口服给药相关的S/R比率变化的活性对映体(真的)有较高的首过代谢率时，建议同时测量总浓度和自对映体的浓度。(Ii)当真的对映体的一次过代谢较低且特定的S/R比率对最佳疗效很重要时，则应分别测定每一对映体。在所有其他情况下，非立体选择性方法应该足够。在考虑立体异构体对BE的影响时，必须考虑两个配方的BE的测试方式。传统的BE研究是基于两个配方、两个顺序、两个周期的设计，其中试验配方和参考配方被给予一组受试者，每个剂量之间有合适的冲洗期。目前的方法是基于
The importance of stereoisomerism in pharmacokinetic, pharmacodynamic, and toxicological studies is now well established and has been the subject of several review articles. 1-12 The impact of stereoisomerism in bioequivalence (BE) studies, however, remains an issue of controversy. 13-21 Those in favor of the use of stereoselective methods in BE studies tend to build their case on theoretical pharmacokinetic, pharmacodynamic, or toxicological grounds and on the fact that stereoselective analytical methods are now available for many chiral drugs. Those against the use of stereoselective methods in all BE studies point out that stereoselective analytical methods are not necessarily facile, and moreover, traditional BE studies are based on crossover designs in which the mixture of isomers is administered in the same proportions to all subjects in whom maximum exposures (Cmax) and extent of exposure (AUC) are compared under identical conditions after administration of the test and reference formulations. Karim16 made a critical appraisal of the first recommendations on the use of stereoselective assays in assessing the BE of racemic drugs proposed by a Swedish regulatory agency in 1991, and on the recommendations that emanated from conference on “Analytical Methods Validation: Bioavailability, BE and Pharmacokinetic Studies” 20 in 1992. The current regulatory guidelines for stereoisomeric drugs in North America, Europe, and Japan have been the subject of a recent comprehensive review by Laganiere. 22 There remains considerable disparity between the different regulatory bodies around the world, however, and the concept of international harmonization on the use of stereoselective methods in BE studies remains an important goal to be realized in the future. A logical starting point for international debate could be a well reasoned algorithm16 for deciding whether stereoselective methods should be used in the assessment of the BE of two formulations of a racemic drug. According to this algorithm (Figure 1), stereoselective methods should be used in two situations:(i) When there is high first pass metabolism of the active enantiomer (eutomer) producing oral input related changes in the S/R ratios, it is suggested that both total and eutomer concentrations should be measured.(ii) When there is low first pass metabolism of the eutomer and when a specific S/R ratio is important for optimal therapeutic effect, then each enantiomer should be measured separately. In all other cases, nonstereoselective methods should suffice.In considering the impact of stereoisomerism on BE it is essential to take into account the manner in which the BE of two formulations is tested. Traditional BE studies are based on two-formulation, two-sequence, two-period designs in which the test and reference formulations are administered to a group of subjects with a suitable washout period between each dose. The current approach is based