Preclinical pharmacokinetics of ranibizumab (rhuFabV2) after a single intravitreal administration
Preclinical pharmacokinetics of ranibizumab (rhuFabV2) after a single intravitreal administration
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DOI：
10.1167/iovs.04-0601
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发表时间：
2005-02-01
影响因子：
4.4
通讯作者：
Shiu, V
中科院分区：
文献类型：
--
作者：
Gaudreault, J;Fei, D;Shiu, V
目的。Ranibizumab （rhuFab V2; Lucentis, Genentech, South San Francisco， CA）是一种人源化单克隆抗体片段，设计用于结合所有形式的VEGF，从而阻断新生血管年龄相关性黄斑变性的血管通透性和血管生成。本研究评估了雷尼单抗在食蟹猴体内单次玻璃体内（ITV）或静脉内（IV）给药后的药代动力学（PK）和血清生物利用度。猴子接受雷尼单抗双侧ITV剂量（500或2000 μ g/只眼，n = 6/组）或单次IV剂量（1000或4000 μ g/只动物，n = 4/组）。在ITV给药后，在几个眼室和血清中测量雷尼单抗浓度10天，在静脉给药后测量48小时。采用室区法和非室区法对药代动力学参数进行了估计。雷尼单抗在所有眼室平行清除，终末半衰期约为3天。它迅速分布到视网膜（6 - 24小时），浓度约为玻璃体的三分之一。注射ITV后，生物利用度(F)为50% ~ 60%。血清浓度非常低，反映了雷尼单抗到达血清后分布更广，清除更快。静脉给药后，终末半衰期约为0.5天。本研究表明，雷尼单抗的PK谱有利于其临床应用，通过每月注射ITV治疗新生血管性AMD。
PURPOSE. Ranibizumab ( rhuFab V2; Lucentis, Genentech, South San Francisco, CA) is a humanized monoclonal antibody fragment designed to bind all forms of VEGF, thereby blocking vessel permeability and angiogenesis in neovascular age- related macular degeneration. This study evaluated the pharmacokinetic ( PK) and serum bioavailability of ranibizumab after a single intravitreal ( ITV) or intravenous ( IV) dose in cynomolgus monkeys.METHODS. Monkeys received ranibizumab as either a bilateral ITV dose ( 500 or 2000 mu g/ eye; n = 6/ group) or a single IV dose ( 1000 or 4000 mu g/ animal; n = 4/ group). After ITV administration, ranibizumab concentrations were measured in several ocular compartments and in serum for 10 days and, after IV administration, for 48 hours. Pharmacokinetic parameters were estimated by compartmental and noncompartmental methods.RESULTS. Ranibizumab cleared in parallel from all ocular compartments, with a terminal half- life of approximately 3 days. It distributed rapidly to the retina ( 6 - 24 hours), and concentrations were approximately one third that in the vitreous. After ITV injection, bioavailability ( F) was 50% to 60%. Serum concentrations were very low, reflecting wider distribution and faster clearance when ranibizumab reached the serum. After IV administration, the terminal half- life was approximately 0.5 day.CONCLUSIONS. This study demonstrates that ranibizumab has a PK profile that is favorable for its clinical use in treating neovascular AMD by monthly ITV injection.