Tissue Pharmacokinetics of Antisense Oligonucleotides

The pharmacokinetics (PK) of antisense oligonucleotides (ASOs) is characterized by rapid distribution from plasma to tissue and by slow terminal plasma elimination, driven by redistribution from tissues. A quantitative understanding of tissue PK and target engagement, as demonstrated by RNA knockdown, is critical for successful drug discovery. This chapter describes and discusses appropriate experimental designs to characterize both the temporal and spatial PK aspects of ASOs. Key considerations, such as the choice of administration route, dosing regimen, single versus repeated dosing, and sampling points are addressed. The chapter also examines mathematical models of varying complexity, from empirical models to physiologically-based pharmacokinetic (PBPK) models, that support the understanding of ASO PK and guide clinical development.