Gaudreault Jacques, Fei David, Rusit Jeriza, Suboc Pamela, Shiu Vanessa
Department of Pharmacokinetic, Genentech Inc., South San Francisco, CA 94080, USA.
Invest Ophthalmol Vis Sci. 2005 Feb;46(2):726-33. doi: 10.1167/iovs.04-0601.
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.
Monkeys received ranibizumab as either a bilateral ITV dose (500 or 2000 microg/eye; n = 6/group) or a single IV dose (1000 or 4000 microg/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.
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.
This study demonstrates that ranibizumab has a PK profile that is favorable for its clinical use in treating neovascular AMD by monthly ITV injection.
雷珠单抗（rhuFab V2；Lucentis，基因泰克公司，加利福尼亚州南旧金山）是一种人源化单克隆抗体片段，旨在结合所有形式的血管内皮生长因子（VEGF），从而在新生血管性年龄相关性黄斑变性中阻断血管通透性和血管生成。本研究评估了食蟹猴单次玻璃体内（ITV）或静脉内（IV）注射雷珠单抗后的药代动力学（PK）和血清生物利用度。
猴子接受雷珠单抗治疗，分为双侧ITV剂量组（500或2000微克/眼；每组n = 6）或单次IV剂量组（1000或4000微克/动物；每组n = 4）。ITV给药后，在10天内测量几个眼内隔室和血清中的雷珠单抗浓度，IV给药后测量48小时。通过房室和非房室方法估计药代动力学参数。
雷珠单抗在所有眼内隔室中平行清除，终末半衰期约为3天。它迅速分布到视网膜（6 - 24小时），浓度约为玻璃体中的三分之一。ITV注射后，生物利用度（F）为50%至60%。血清浓度非常低，这反映出雷珠单抗进入血清后分布更广泛且清除更快。IV给药后，终末半衰期约为0.5天。
本研究表明，雷珠单抗的药代动力学特征有利于其通过每月一次的ITV注射在治疗新生血管性年龄相关性黄斑变性中的临床应用。
