Emerging siRNA Design Principles and Consequences for Biotransformation and Disposition in Drug Development.,Journal of Medicinal Chemistry

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Emerging siRNA Design Principles and Consequences for Biotransformation and Disposition in Drug Development.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-04-30 , DOI: 10.1021/acs.jmedchem.9b01839
Sara C Humphreys ₁ , Mai B Thayer ₁ , Jabbar Campbell ₂ , Wen Li Kelly Chen ₃ , Dan Adams ₃ , Julie M Lade ₁ , Brooke M Rock ₁

Affiliation

After two decades teetering at the intersection of laboratory tool and therapeutic reality, with two siRNA drugs now clinically approved, this modality has finally come into fruition. Consistent with other emerging modalities, initial proof-of-concept efforts concentrated on coupling pharmacologic efficacy with desirable safety profiles. Consequently, thorough investigations of siRNA absorption, distribution, metabolism, and excretion (ADME) properties are lacking. Advancing ADME knowledge will aid establishment of in vitro–in vivo correlations and pharmacokinetic–pharmacodynamic relationships to optimize candidate selection through discovery and translation. Here, we outline the emerging siRNA design principles and discuss the consequences for siRNA disposition and biotransformation. We propose a conceptual framework for siRNA ADME evaluation, contextualizing the site of biotransformation product formation with PK–PD modulation, and end with a discussion around safety and regulatory considerations and future directions for this modality.

中文翻译：

新兴的siRNA设计原则和在药物开发中进行生物转化和处理的后果。

在实验室工具和治疗现实的交织处徘徊了二十年之后，随着两种siRNA药物现已获得临床批准，这种治疗方法终于得以实现。与其他新出现的方法相一致，概念验证的最初工作集中于将药理功效与所需的安全性相结合。因此，缺乏对siRNA吸收，分布，代谢和排泄（ADME）特性的深入研究。增强ADME知识将有助于建立体外-体内相关性和药代动力学-药效关系，以通过发现和翻译来优化候选者的选择。在这里，我们概述了新兴的siRNA设计原则，并讨论了siRNA处置和生物转化的后果。我们提出了一个用于siRNA ADME评估的概念框架，结合了PK-PD调控对生物转化产物形成的位置进行了背景分析，最后围绕安全性和监管考虑以及该模式的未来方向进行了讨论。

更新日期：2020-06-25

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