Application and Challenges of Pharmacometrics in siRNAs

The speaker will provide an overview of small interfering RNA (siRNA), highlighting its general properties and key absorption, distribution, metabolism, and excretion (ADME) and pharmacodynamic (PD) characteristics in contrast to other therapeutic modalities. These unique properties present both opportunities and challenges for model-informed drug development (MIDD), which will be explored through relevant case studies. siRNA exhibits rapid distribution, a long half-life (t₁/₂), and an even longer PD effect. A key challenge in PK/PD modeling is the undetectable systemic exposure within one to two days post-dose, despite PD effects persisting for several months. To address this, pharmacokinetic-driven (PKD) approaches have been utilized to support drug development. Additionally, the kinetics of PD as well as its correlation with clinical endpoints may be used to inform clinical design. MIDD has been applied at all stages of siRNA drug development, from preclinical to clinical phases. This presentation will include simulation examples and case studies demonstrating the role of MIDD in interspecies scaling for first-in-human dose selection and dose optimization across clinical stages, as well as challenges in MIDD.