PK and Clinical Pharmacology (N.P., R.Y., S.G., J.M., Y.W.) and Medicinal Chemistry (H.G.), Ionis Pharmaceuticals, Inc., Carlsbad, California; and PK and Clinical Pharmacology, Akcea Therapeutics, Boston, Massachusetts (E.H.)
PK and Clinical Pharmacology (N.P., R.Y., S.G., J.M., Y.W.) and Medicinal Chemistry (H.G.), Ionis Pharmaceuticals, Inc., Carlsbad, California; and PK and Clinical Pharmacology, Akcea Therapeutics, Boston, Massachusetts (E.H.).
Drug Metab Dispos. 2019 Oct;47(10):1164-1173. doi: 10.1124/dmd.119.087395. Epub 2019 Jul 26.
Volanesorsen (previously known as ISIS 304801) is a 20-nucleotide partially 2'--(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 [H]-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. SIGNIFICANCE STATEMENT: 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 H rat ADME study, and a phase 1 clinical trial.
伏拉索森（以前称为 ISIS 304801）是一种 20 个核苷酸的部分 2'-（2-甲氧基乙基）（2'-MOE）修饰的反义寡核苷酸（ASO），最近在欧盟被批准用于治疗家族性乳糜微粒血症综合征患者的甘油三酯水平降低，是一种新型的首创治疗方法。我们在小鼠、大鼠、猴子和人类中进行了伏拉索森的吸收、分布、代谢和排泄特征的研究，包括放射性标记或非放射性标记研究。这还包括了在尿液中排泄的所有观察到的 ASO 代谢产物的特征描述。伏拉索森与小鼠、猴子和人类的血浆蛋白高度结合。在所有物种中，血浆浓度呈多相下降，其特征是初始分布阶段相对较快，然后在皮下推注后，终末消除阶段较慢。伏拉索森的血浆代谢产物谱在各物种中相似，伏拉索森是主要成分。在多次给药的小鼠和猴子研究中，在组织中鉴定出各种缩短的寡核苷酸代谢物（5-19 个核苷酸长），而在 [H]-伏拉索森大鼠研究中则较少，这可能是由于大鼠单次给药后代谢物的积累较少。在尿液中，观察到在组织中鉴定出的所有代谢物，这与内切酶和外切酶介导的代谢以及尿液排泄是伏拉索森及其代谢物的主要消除途径一致。意义陈述：我们利用从临床前毒理学研究、H 大鼠 ADME 研究和 I 期临床试验中收集的样本中使用的新型提取和定量技术，对伏拉索森（一种部分 2'-MOE 修饰的反义寡核苷酸）的吸收、分布、代谢和排泄（ADME）进行了特征描述。
