Introduction: Advances in research and development (R&D) have enabled many approvals of antisense oligonucleotides (ASOs). Its administration expanded from systemic to local for treating various diseases, where predicting target tissue exposures and pharmacokinetics (PK) and pharmacodynamics (PD) in human can be critical.
Areas covered: A literature search for PBPK/PD models of ASOs was conducted using PubMed and Embase (to 1 April 2023). ASO PK and PD in animals and humans and modeling approaches including physiologically based (PB) are summarized; and relevance and impacts of PBPK/PD modeling are assessed.
Expert opinion: Allometric scaling and compartmental PK/PD modeling have been successful to predict human ASO PK/PD, addressing most R&D needs. Understanding tissue distribution of ASOs can be crucial for their efficacy and safety especially for intrathecal (IT), pulmonary, or other local routes. PBPK/PD modeling is expected to improve such understanding, for which, efforts have been sporadic. However, developing a PBPK/PD model requires careful review of known biology/pharmacology and thoughtful experimental designs. Resulting models have the potential to predict target/specified tissue exposures and responses in human adults and pediatrics. Ultimately, a PBPK/PD modeling approach can lead to more efficient and rational clinical development, resulting in well-informed decision making and a shortened timeline.
Keywords: Antisense oligonucleotide; pharmacodynamics; pharmacokinetics; physiologically-based modeling; prediction of human effects.