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首页> 外文期刊>Drug discovery today >Better prediction of the local concentration-effect relationship: the role of physiologically based pharmacokinetics and quantitative systems pharmacology and toxicology in the evolution of model-informed drug discovery and development
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Better prediction of the local concentration-effect relationship: the role of physiologically based pharmacokinetics and quantitative systems pharmacology and toxicology in the evolution of model-informed drug discovery and development

机译：更好地预测局部集中效应关系：生理基础的药代动力学和定量系统药理和毒理学在模型知识药物发现和发展中的作用

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摘要

Model-informed drug discovery and development (MID3) is an umbrella term under which sit several computational approaches: quantitative systems pharmacology (QSP), quantitative systems toxicology (QST) and physiologically based pharmacokinetics (PBPK). QSP models are built using mechanistic knowledge of the pharmacological pathway focusing on the putative mechanism of drug efficacy; whereas QST models focus on safety and toxicity issues and the molecular pathways and networks that drive these adverse effects. These can be mediated through exaggerated on target or off-target pharmacology, immunogenicity or the physiochemical nature of the compound. PBPK models provide a mechanistic description of individual organs and tissues to allow the prediction of the intra- and extra-cellular concentration of the parent drug and metabolites under different conditions. Information on biophase concentration enables the prediction of a drug effect in different organs and assessment of the potential for drug-drug interactions. Together, these modelling approaches can inform the exposure-response relationship and hence support hypothesis generation and testing, compound selection, hazard identification and risk assessment through to clinical proof of concept (POC) and beyond to the market.
机译：模型知识的药物发现和发展（MID3）是一种占地几种计算方法：定量系统药理（QSP），定量系统毒理学（QST）和生理基础的药代动力学（PBPK）。 QSP模型是利用药理学途径的机械知识构建，重点是药物疗效的推定机制; QST模型专注于安全性和毒性问题以及驱动这些不利影响的分子途径和网络。这些可以通过夸大的靶或脱靶药理学，免疫原性或化合物的生理化学性质来介导。 PBPK模型提供了个体器官和组织的机械描述，以允许在不同条件下预测母体药物和代谢物的内部和额外细胞浓度。有关生物酶浓度的信息使得能够预测不同器官的药物作用和对药物 - 药物相互作用的可能性的评估。这些建模方法可以通知曝光 - 响应关系，因此支持假设生成和测试，复合选择，危害识别和风险评估到临床概念（POC）及以后的市场。

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  • 来源
    《Drug discovery today》 |2019年第7期|共11页
  • 作者

    Polak Sebastian; Tylutki Zofia; Holbrook Mark; Wisniowska Barbara;

  • 作者单位

    Jagiellonian Univ Med Coll Fac Pharm Med 9 St PL-30688 Krakow Poland;

    Jagiellonian Univ Med Coll Fac Pharm Med 9 St PL-30688 Krakow Poland;

    Certara Simcyp Level 2 Acero 1 Concourse Way Sheffield S1 2BJ S Yorkshire England;

    Jagiellonian Univ Med Coll Fac Pharm Med 9 St PL-30688 Krakow Poland;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药学;
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