Pharmacokinetics of a tumor necrosis factor-α phosphorothioate 2′-O-(2-methoxyethyl) modified antisense oligonucleotide:: Comparison across species
Pharmacokinetics of a tumor necrosis factor-α phosphorothioate 2′-O-(2-methoxyethyl) modified antisense oligonucleotide:: Comparison across species
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DOI：
10.1124/dmd.31.11.1419
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发表时间：
2003-11-01
影响因子：
3.9
通讯作者：
Levin, AA
中科院分区：
文献类型：
--
作者：
Geary, RS;Yu, RZ;Levin, AA
已在小鼠、大鼠、犬、猴和人中表征了2 '-O-（2-甲氧基乙基）-核糖修饰的硫代磷酸酯寡核苷酸ISIS 104838（人肿瘤坏死因子-α反义）的药代动力学。静脉给药后的血浆药代动力学显示从血浆到组织的分布相对较快，所有种属的分布半衰期估计约为15 - 45 min。s.c.后吸收注射后的吸收率高（80 - 100%），与静脉内给药相比，以专利制剂空肠内给药后的吸收率高达10%。母体药物的尿液排泄量较低，猴以临床相关剂量（≤ 5 mg/ kg）静脉输注后，尿液中排泄的母体药物剂量不到给药剂量的1%。ISIS 104838与血浆蛋白高度结合，可能阻止肾滤过。然而，ISIS 104838的缩短的寡核苷酸代谢物失去其结合血浆蛋白的亲和力。因此，到90天时，尿液（75%）和粪便（5 - 10%）中的放射性标记物（主要为代谢物）几乎完全排泄。根据组织或器官，所有种属的ISIS 104838从组织中消除缓慢（数天）。在肾脏、肝脏、淋巴结、骨髓和脾脏中观察到组织中ISIS 104838的最高浓度。一般而言，在体重等效剂量下，猴组织中ISIS 104838的浓度高于啮齿类动物。血浆药代动力学在各物种间的比例很好，仅作为体重的函数。ISIS 104838的这种有利的药代动力学特征为临床开发提供了指导，似乎支持不频繁和方便的给药。
The pharmacokinetics of a 2'-O-(2-methoxyethyl)-ribose modified phosphorothioate oligonucleotide, ISIS 104838 ( human tumor necrosis factor-alpha antisense), have been characterized in mouse, rat, dog, monkey, and human. Plasma pharmacokinetics after i.v. administration exhibited relatively rapid distribution from plasma to tissues with a distribution half-life estimated from approximately 15 to 45 min in all species. Absorption after s.c. injection was high (80 - 100%), and absorption after intrajejunal administration in proprietary formulations was as high as 10% bioavailability compared with i.v. administration. Urinary excretion of the parent drug was low, with less than 1% of the administered dose excreted in urine after i.v. infusion in monkeys at clinically relevant doses (less than or equal to5 mg/ kg). ISIS 104838 is highly bound to plasma proteins, likely preventing renal filtration. However, shortened oligonucleotide metabolites of ISIS 104838 lose their affinity to bind plasma proteins. Thus, excretion of radiolabel (mostly as metabolites) in urine (75%) and feces (5 - 10%) was nearly complete by 90 days. Elimination of ISIS 104838 from tissue was slow ( multiple days) for all species, depending on the tissue or organ. The highest concentrations of ISIS 104838 in tissues were seen in kidney, liver, lymph nodes, bone marrow, and spleen. In general, concentrations of ISIS 104838 were higher in monkey tissues than in rodents at body weight-equivalent doses. Plasma pharmacokinetics scale well across species as a function of body weight alone. This favorable pharmacokinetic profile for ISIS 104838 provides guidance for clinical development and appears to support infrequent and convenient dose administration.