Tissue pharmacokinetics of antisense oligonucleotides

Abstract

Pharmacokinetics of antisense oligonucleotides (ASO) is characterized by rapid distribution from plasma to tissue and slow terminal plasma elimination driven by re-distribution from tissue. Quantitative understanding of tissue pharmacokinetics and RNA knockdown for various ASO chemistries, conjugations and administration routes is critical for successful drug discovery. Here, we report concentration-time and RNA knockdown profiles for a gapmer ASO with locked nucleic acid ribose chemistry in mouse liver, kidney, heart, and lung after subcutaneous and intratracheal administration. Additionally, the same ASO with liver targeting conjugation (galactosamine-N-acetyl) is evaluated for subcutaneous administration. Data indicate that exposure and knockdown differ between tissues, and strongly depends on administration route and conjugation. In a second study, we show that tissue pharmacokinetics is similar between the three different ribose chemistries locked nucleic acid, constrained ethyl and 2′-O-methoxyethyl, both after subcutaneous and intratracheal administration. Further, we show that the half-life in mouse liver may vary with ASO sequence. Finally, we report less than dose-proportional increase in liver concentration in the dose range 3 to 30 μmol/kg. Overall, our studies contribute pivotal data to support design and interpretation of ASO in vivo studies, thereby increasing the probability of delivering novel ASO therapies to patients.