Efficacy of Lenvatinib, a multitargeted tyrosine kinase inhibitor, on laser-induced CNV mouse model of neovascular AMD. (March 2018)

• Record Type: Journal Article
• Authors: Wei, Xian; Zhang, Ting; Yao, Yuqin; Zeng, Shaoxue; Li, Min; Xiang, Haotian; Zhao, Chengjian; Cao, Guiqun; Li, Minhui; Wan, Ran; Yang, Ping; Yang, Jinliang
• Is Part Of: Experimental eye research. Volume 168(2018)
• Page Start: 2
• Page End: 11
• Publication Date: 2018-03
• Subjects: Neovascular AMD -- Choroidal neovascularization -- Lenvatinib -- Angiogenesis -- tyrosine kinase inhibitor -- LC/MS/MS -- Retina; Ophthalmology -- Periodicals; Eye -- Periodicals; Œil -- Périodiques; Ophthalmology; Periodicals; Electronic journals; 612.8405
• DOI: 10.1016/j.exer.2017.12.009
• Languages: English
• ISSNs: 0014-4835

Abstract

Abstract: Neovascular age-related macular degeneration (AMD) is a leading cause of vision loss worldwide. Although intravitreal injection of anti-VEGF antibodies and VEGF Trap have significant clinical benefits, the complications of intravitreal injection, drug resistance and patient compliance still need to be concerned. In this study, the effects of an orally administered multi-targeted tyrosine kinase inhibitor (Lenvatinib, E7080) were evaluated in vitro and in vivo on neovascular AMD mouse model. The results showed that E7080 effectively inhibited the proliferation, migration and tubule formation of human choroidal microvascular endothelial cells (HCMECs), and suppressed the angiogenesis of zebrafish subintestinal vessels without causing malformation. The anti-angiogenic effect of E7080 on the laser-induced choroidal neovascularization (CNV) mouse model by oral administration of 10 mg/kg/day was observed. The fluorescein angiography showed CNV leakage area in treatment group vs control group was 3.407 ± 0.2939 vs 5.202 ± 0.9001 ( P = .0133) at day 7th post laser-induced CNV, 1.138 ± 0.4334 vs 3.122 ± 0.3466 ( P = .0064) at day 14th, 1.401 ± 0.6577 vs 2.781 ± 0.9815 ( P = .00262) at day 21th respectively. Moreover, pharmacokinetics analysis in rat retina showed that E7080 rapidly penetrated the blood-retina barrier to retina through oral administration. The T1/2 in retina was 3.81 ± 0.77 h, the Tmax was 4.60 ± 0.73 h, the AUC0-∞ was 110448.51 ± 18532.51 h*ng/g after a single dose administration analyzed by liquid chromatography-tandem mass spectrometry (LC/MS/MS). In conclusion, our study suggested that orally administered E7080 can be a novel therapeutic strategy for neovascular AMD. Highlights: Oral Lenvatinib shown significantly benefit on neovascular AMD mouse model. Lenvatinib inhibited the proliferation, migration, tubule formation of HCMECs. Lenvatinib inhibited zebrifish SIV angiogenesis. Lenvatinib takes effect in ocular fundus by penetrating the blood-retina barrier. Oral Lenvatinib may be a potential candidate for therapy of neovascular AMD.