Cross-species comparison of in vivo PK/PD relationships for second-generation antisense oligonucleotides targeting apolipoprotein B-100
Cross-species comparison of in vivo PK/PD relationships for second-generation antisense oligonucleotides targeting apolipoprotein B-100
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DOI：
10.1016/j.bcp.2008.11.005
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发表时间：
2009-03-01
影响因子：
5.8
通讯作者：
Geary, Richard S.
中科院分区：
文献类型：
--
作者：
Yu, Rosie Z.;Lemonidis, Kristina M.;Geary, Richard S.
在多个种属中表征了靶向载脂蛋白B-100（apo B-100）的2 '-O-（2-甲氧基乙基）（2'-莫伊）修饰的反义寡核苷酸（ASO）的体内药代动力学/药效学。种属特异性apoB反义抑制剂在小鼠、猴和人中表现出靶向apoB mRNA以药物浓度和时间依赖性方式降低。与肝脏apoB mRNA的浓度依赖性降低一致，在动物模型和人体中同时观察到血清apoB、LDL-C和总胆固醇降低。此外，停止给药后的长效应持续时间与在小鼠（t（1/2）等于20天）和人（t（1/2）等于30天）中研究的胃肠外给药后2 '-莫伊修饰的apoB ASO的消除半衰期密切相关。在小鼠和猴的终末消除期观察到的ISIS 301012血浆浓度与肝脏平衡。不同种属间肝脏和血浆之间的分配比相似，约为6000：1，因此可作为人体组织暴露的替代物。使用抑制性E-max模型，在高脂喂养（HF）小鼠、含有人apoB转基因的转基因小鼠和猴中，阿索肝脏EC 50分别为101 +/- 32、119 +/- 15和300 +/- 191 μ g/g阿索。根据血浆谷值暴露量外推的人体肝脏EC 50估计值为81 +/- 122 μ g/g。因此，在包括人在内的物种中观察到apoB反义抑制剂的确定性-反应关系的显著一致性。跨种属PK/PD关系为使用药理学动物模型预测靶向肝脏的第二代ASO的人体给药提供了信心。(C)2008年爱思唯尔公司All rights reserved.
The in vivo pharmacokinetics/pharmacodynamics of 2'-O-(2-methoxyethyl) (2'-MOE) modified antisense oligonucleotides (ASOs), targeting apolipoprotein B-100 (apoB-100), were characterized in multiple species. The species-specific apoB antisense inhibitors demonstrated target apoB mRNA reduction in a drug concentration and time-dependent fashion in mice, monkeys, and humans. Consistent with the concentration-dependent decreases in liver apoB mRNA, reductions in serum apoB, and LDL-C, and total cholesterol were concurrently observed in animal models and humans. Additionally, the long duration of effect after cessation of dosing correlated well with the elimination half-life of 2'-MOE modified apoB ASOs studied in mice (t(1/2) congruent to 20 days) and humans (t(1/2) congruent to 30 days) following parental administrations. The plasma concentrations of ISIS 301012, observed in the terminal elimination phase of both mice and monkeys were in equilibrium with liver. The partition ratios between liver and plasma were similar, approximately 6000:1, across species, and thus provide a surrogate for tissue exposure in humans. Using an inhibitory E-max model, the ASO liver EC50s were 101 +/- 32, 119 +/- 15, and 300 +/- 191 mu g/g of ASO in high-fat-fed (HF) mice, transgenic mice containing the human apoB transgene, and monkeys, respectively. The estimated liver EC50 in man, extrapolated from trough plasma exposure, was 81 +/- 122 mu g/g. Therefore, extraordinary consistency of the exposure-response relationship for the apoB antisense inhibitor was observed across species, including human. The cross-species PK/PD relationships provide confidence in the use of pharmacology animal models to predict human dosing for second-generation ASOs targeting the liver. (C) 2008 Elsevier Inc. All rights reserved.