ADME Attributes of siRNAs and Translational PK/PD Approaches

Small-interfering RNA (siRNA) represents a new class of drug molecules with the potential to be transformative for patients. By leveraging a natural process that silences genes, these molecules can effectively inhibit the production of disease-causing proteins. siRNAs typically have a molecular weight of around 15 kDa and carry negative charges at physiological pH. These physicochemical properties result in distinct ADME (Absorption, Distribution, Metabolism, and Excretion) characteristics that are different from those of small molecules or monoclonal antibodies. For instance, siRNAs depend on carrier-mediated uptake to reach their target cells, and they are metabolized by endo- and exonucleases, which are generally conserved across species. Their enrichment and slow release from endosomes result in long-lasting pharmacodynamic effects, even though they have a short half-life in circulation. With these unique attributes, platform learnings can be applied to siRNAs using the same delivery methods aimed at the same target organs (e.g., the liver). This presentation will summarize the accumulated knowledge regarding the ADME properties of siRNAs and highlight translational pharmacokinetics/pharmacodynamics (PK/PD) approaches that quantitatively integrate nonclinical data to inform clinical development plans.