Scaling factors to inform in vitro-in vivo extrapolation from preclinical and livestock animals: state of the field and recommendations for development of missing data.

IF 3.4 2区 医学 Q2 PHARMACOLOGY & PHARMACY
Austin A Zimmer, Abby C Collier
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引用次数: 0

Abstract

The use of in-vitro-in-vivo physiologically based pharmacokinetic (IVIVE-PBPK) modeling approaches assists for prediction of first-in animal or human trials. These approaches are underpinned by the scaling factors: microsomal protein per gram (MPPG) and cytosolic protein per gram (CPPG). In addition, IVIVE-PBPK has significant application in the reduction and refinement of live animal models in research. While human scaling factors are well-defined, many preclinical and livestock species remain poorly elucidated or uncharacterized. The MPPG parameter for liver (MPPGL) is the best characterized across all species and is well-defined for mouse, rat, and dog models. The MPPG parameters for Kidney (MPPGK) and intestine (MPPGI), are however; relatively indefinite for most species. Similarly, CPPG scaling factors for liver, kidney, and intestine (CPPGL/CPPGK/CPPGI) are generally sparse in all species. In addition to generation of mathematical values for scaling factors, methodological and animal-specific considerations, such as age, sex, and strain differences, have not yet been comprehensively described. Here, we review the current state-of-the-field for microsomal and cytosolic scaling factors, including highlighting areas that may need further description and development, with the intention of drawing attention to key knowledge gaps. The intention is to promote improved accuracy and precision in IVIVE-PBPK, concordance between laboratories, and stimulate work in underserved, but increasingly vital areas.

从临床前和家畜进行体内外推的比例因子:领域现状和缺失数据的发展建议。
体外体内基于生理的药代动力学(IVIVE-PBPK)建模方法的使用有助于预测首次动物或人体试验。这些方法的基础是缩放因子:每克微粒体蛋白(MPPG)和每克细胞质蛋白(CPPG)。此外,IVIVE-PBPK在研究中活体动物模型的还原和细化方面具有重要的应用。虽然人类的比例因子被很好地定义,但许多临床前和牲畜物种仍然很不清楚或未表征。肝脏的MPPG参数(MPPGL)在所有物种中都是最具特征的,并且在小鼠、大鼠和狗模型中定义良好。然而,肾脏(MPPGK)和肠道(MPPGI)的MPPG参数为;对大多数物种来说相对不确定。同样,在所有物种中,肝、肾和肠的CPPG比例因子(CPPGL/CPPGK/CPPGI)也普遍稀疏。除了生成比例因子的数学值外,方法学和动物特定的考虑因素,如年龄、性别和品系差异,尚未得到全面描述。在这里,我们回顾了微粒体和细胞质比例因子的现状,包括强调可能需要进一步描述和发展的领域,目的是提请注意关键的知识差距。目的是促进提高IVIVE-PBPK的准确性和精密度,实验室之间的一致性,并刺激服务不足但日益重要的领域的工作。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Drug Metabolism Reviews
Drug Metabolism Reviews 医学-药学
CiteScore
11.10
自引率
1.70%
发文量
21
审稿时长
1 months
期刊介绍: Drug Metabolism Reviews consistently provides critically needed reviews of an impressive array of drug metabolism research-covering established, new, and potential drugs; environmentally toxic chemicals; absorption; metabolism and excretion; and enzymology of all living species. Additionally, the journal offers new hypotheses of interest to diverse groups of medical professionals including pharmacologists, toxicologists, chemists, microbiologists, pharmacokineticists, immunologists, mass spectroscopists, as well as enzymologists working in xenobiotic biotransformation.
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