Emerging siRNA Design Principles and Consequences for Biotransformation and Disposition in Drug Development
| Autor: | Mai B. Thayer, Brooke M. Rock, Jabbar Campbell, Sara C. Humphreys, Dan Adams, Wen Li Kelly Chen, Julie M. Lade |
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| Rok vydání: | 2020 |
| Předmět: |
Drug Evaluation
Preclinical Design elements and principles Computational biology 01 natural sciences 03 medical and health sciences Drug Development Biotransformation Drug Discovery Animals Humans Tissue Distribution Product formation Tissue distribution RNA Small Interfering 030304 developmental biology ADME 0303 health sciences Chemistry Disposition 0104 chemical sciences 010404 medicinal & biomolecular chemistry Pharmaceutical Preparations Drug development Drug Design Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 63:6407-6422 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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