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Molecular therapy. Nucleic acids
Mar 12, 2024;35 (1): 102133.

Tissue pharmacokinetics of antisense oligonucleotides.

Erica Bäckström, Alessandro Bonetti, Per Johnsson, Stefan Öhlin, Anders Dahlén, Patrik Andersson, Shalini Andersson, Peter Gennemark
Author Information
  1. Erica Bäckström: Drug Metabolism and Pharmacokinetics, Research and Early Development, Respiratory & Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, 431 83 Gothenburg, Sweden.
  2. Alessandro Bonetti: Oligonucleotide Discovery, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, 431 83 Gothenburg, Sweden.
  3. Per Johnsson: Oligonucleotide Discovery, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, 431 83 Gothenburg, Sweden.
  4. Stefan Öhlin: Business, Planning Operations, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, 431 83 Gothenburg, Sweden.
  5. Anders Dahlén: Oligonucleotide Discovery, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, 431 83 Gothenburg, Sweden.
  6. Patrik Andersson: Safety Innovation, Safety Sciences, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, 431 83 Gothenburg, Sweden.
  7. Shalini Andersson: Oligonucleotide Discovery, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, 431 83 Gothenburg, Sweden.
  8. Peter Gennemark: Drug Metabolism and Pharmacokinetics, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, 431 83 Gothenburg, Sweden.
PMID: 38419941 DOI: 10.1016/j.omtn.2024.102133

Abstract

Pharmacokinetics (PK) of antisense oligonucleotides (ASOs) is characterized by rapid distribution from plasma to tissue and slow terminal plasma elimination driven by re-distribution from tissue. Quantitative understanding of tissue PK 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--acetyl) is evaluated for subcutaneous administration. Data indicate that exposure and knockdown differ between tissues and strongly depend on administration route and conjugation. In a second study, we show that tissue PK is similar between the three different ribose chemistries locked nucleic acid, constrained ethyl and 2'--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 of 3-30 μmol/kg. Overall, our studies contribute pivotal data to support design and interpretation of ASO studies, thereby increasing the probability of delivering novel ASO therapies to patients.

Keywords

MT: oligonucleotides: therapies and applications antisense oligonucleotides distribution dose proportional mouse pharmacokinetics tissue

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