Disposition and Pharmacokinetics of a GalNAc3-Conjugated Antisense Oligonucleotide Targeting Human Lipoprotein (a) in Monkeys
| Autor: | Mark J. Graham, Rosie Z. Yu, Eric E. Swayze, Rudy Gunawan, Shannon Hall, Richard S. Geary, Jennifer Burkey, Noah Post, Scott P. Henry, Thomas A. Zanardi, Thazha P. Prakash, Punit P. Seth, Yanfeng Wang, Tae-Won Kim |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Acetylgalactosamine Injections Subcutaneous Cmax Phosphorothioate Oligonucleotides Pharmacology Biochemistry 03 medical and health sciences chemistry.chemical_compound Pharmacokinetics Drug Discovery Genetics medicine Distribution (pharmacology) Potency Animals Molecular Biology Biotransformation RNA Cleavage Oligonucleotide Chemistry Blood Proteins Oligonucleotides Antisense 030104 developmental biology medicine.anatomical_structure Liver Hepatocyte Galactosamine Hepatocytes Molecular Medicine Female Glycoconjugates Lipoprotein Half-Life Lipoprotein(a) Protein Binding |
| Zdroj: | Nucleic acid therapeutics. 26(6) |
| ISSN: | 2159-3345 |
| Popis: | Triantennary N-acetyl galactosamine (GalNAc3)-conjugated antisense oligonucleotides (ASOs) have greatly improved potency due to receptor-mediated uptake into hepatocyte. The disposition and pharmacokinetics of ISIS 681257, a GalNAc3-conjugated ASO, were studied in monkeys. Following subcutaneous (SC) injection, ISIS 681257 was rapidly absorbed into the systemic circulation, with peak plasma levels observed within hours after dosing. After reaching Cmax, plasma concentrations rapidly declined in a multiexponential manner and were characterized by a dominant initial rapid distribution phase in which drug transferred to tissues from circulation, followed by a much slower terminal elimination phase (half-life of 4 weeks). Intact ISIS 681257 is the major full-length oligonucleotide species in plasma (≥70%). In tissues, the conjugated-GalNAc sugar moiety was rapidly metabolized, leaving the fully unconjugated form as the only full-length oligonucleotide detected at 48 h after dosing. Unconjugated ISIS 681257 cl... |
| Databáze: | OpenAIRE |
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