ISSX: 16th European Meeting | From Benchside Research to Bedside Reality: DMPK's Next Chapter

This presentation aims to share key considerations for DMPK strategies during the preclinical development of brain-targeted therapeutics. Key takeaways will include:

• Complexity and challenges in exposure assessment of brain-targeted drugs

• Leveraging the advantages of humanized animal models to optimize PK strategies for brain-targeted drugs

• Preclinical DMPK approaches to support the development of novel drug delivery technologies for brain-targeted therapeutics

Accurate in vitro plasma protein binding (PPB) assessment is crucial for predicting the distribution, safety, and efficacy of oligonucleotide therapeutics. However, the literature reveals striking discrepancies in siRNA PPB data, largely driven by the choice of assay methodology. This presentation explores the fundamental differences and methodological artifacts between the two predominantly used formats: Ultrafiltration (UF) and Electrophoretic Mobility Shift Assay (EMSA). We will delve into strategies to overcome severe non-specific binding (NSB) in UF and expose the dynamic, condition-dependent artifacts inherent in EMSA. By systematically unraveling these discrepancies, we provide a robust, optimized methodological framework for reliable, regulatory-compliant PPB evaluations, ultimately guiding more accurate ADME profiling in oligonucleotide drug development.