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• W2964754110 abstract "Volanesorsen (previously known as ISIS 304801) is a 20-nucleotide partially 2′-<i>O</i>-(2-methoxyethyl) (2′-MOE)–modified antisense oligonucleotide (ASO) gapmer, which was recently approved in the European Union as a novel, first-in-class treatment in the reduction of triglyceride levels in patients with familial chylomicronemia syndrome. We characterized the absorption, distribution, metabolism, and excretion characteristics of volanesorsen in mice, rats, monkeys, and humans, in either radiolabeled or nonradiolabeled studies. This also included the characterization of all of the observed ASO metabolite species excreted in urine. Volanesorsen is highly bound to plasma proteins that are similar in mice, monkeys, and humans. In all species, plasma concentrations declined in a multiphasic fashion, characterized by a relatively fast initial distribution phase and then a much slower terminal elimination phase following subcutaneous bolus administration. The plasma metabolite profiles of volanesorsen are similar across species, with volanesorsen as the major component. Various shortened oligonucleotide metabolites (5–19 nucleotides long) were identified in tissues in the multiple-dose mouse and monkey studies, but fewer in the [³H]-volanesorsen rat study, likely due to a lower accumulation of metabolites following a single dose in rats. In urine, all metabolites identified in tissues were observed, consistent with both endo- and exonuclease-mediated metabolism and urinary excretion being the major elimination pathway for volanesorsen and its metabolites. <h3>Significance Statement</h3> We characterized the absorption, distribution, metabolism, and excretion (ADME) of volanesorsen, a partially 2′-MOE–modified antisense oligonucleotide, from mouse to man utilizing novel extraction and quantitation techniques in samples collected from preclinical toxicology studies, a ³H rat ADME study, and a phase 1 clinical trial." @default.
• W2964754110 created "2019-08-13" @default.
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• W2964754110 date "2019-07-26" @default.
• W2964754110 modified "2023-10-16" @default.
• W2964754110 title "Metabolism and Disposition of Volanesorsen, a 2′-<i>O</i>-(2 methoxyethyl) Antisense Oligonucleotide, Across Species" @default.
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• W2964754110 doi "https://doi.org/10.1124/dmd.119.087395" @default.
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