R&D Division Kyowa Kirin Co., Ltd. Sunto-gun Shizuoka Japan.
Department of Clinical Pharmaceutics School of Pharmaceutical Sciences University of Shizuoka Sunto-gun Shizuoka Japan.
Pharmacol Res Perspect. 2019 Nov 20;7(6):e00545. doi: 10.1002/prp2.545. eCollection 2019 Dec.
Age-related macular degeneration (AMD) is the leading cause of severe vision impairment in patients over the age of 60 years. Choroidal neovascularization (CNV) is the hallmark of neovascular AMD and vascular endothelial growth factor (VEGF) plays a causal role in the formation of CNV. Although regorafenib and pazopanib, small molecule VEGF receptor (VEGFR) inhibitors, were developed as eye-drops, their efficacies were insufficient in clinical. In this study, we evaluated ocular pharmacokinetics and pharmacological activities of regorafenib and pazopanib after ocular instillation in multiple animal species. In rats, both regorafenib and pazopanib showed high enough concentrations in the posterior eye tissues to inhibit VEGFR. In laser-induced rat CNV model, regorafenib showed clear reduction in CNV area. On the other hand, the concentrations of regorafenib and pazopanib in the posterior eye tissues were much lower after ocular instillation in rabbits and monkeys compared to those in rats. Pazopanib did not show any improvement in monkey model. Regorafenib was nano-crystalized to improve its drug delivery to the posterior eye tissues. The nano-crystalized formulation of regorafenib showed higher concentrations in the posterior segments in rabbits compared to its microcrystal suspension. From these studies, large interspecies differences were found in ocular delivery to the posterior segments after ocular instillation. Such large interspecies difference could be the reason for the insufficient efficacies of regorafenib and pazopanib in clinical studies. Nano-crystallization was suggested to be one of the effective ways to overcome this issue.
年龄相关性黄斑变性（AMD）是 60 岁以上患者严重视力损害的主要原因。脉络膜新生血管（CNV）是新生血管性 AMD 的标志，血管内皮生长因子（VEGF）在 CNV 的形成中起因果作用。尽管regorafenib 和 pazopanib 是小分子血管内皮生长因子受体（VEGFR）抑制剂，被开发为滴眼剂，但它们在临床中的疗效不足。在这项研究中，我们评估了 regorafenib 和 pazopanib 滴眼后在多种动物物种中的眼部药代动力学和药理活性。在大鼠中，regorafenib 和 pazopanib 在后眼组织中的浓度均足够高，可抑制 VEGFR。在激光诱导的大鼠 CNV 模型中，regorafenib 明显减少了 CNV 面积。另一方面，与大鼠相比，兔和猴滴眼后，regorafenib 和 pazopanib 在后眼组织中的浓度要低得多。pazopanib 在猴模型中没有任何改善。regorafenib 被纳米晶化以改善其向眼后组织的药物传递。与微晶体混悬剂相比，纳米晶化的 regorafenib 制剂在兔的后段中显示出更高的浓度。从这些研究中发现，滴眼后向眼后段的眼部传递在种间存在很大差异。这种大的种间差异可能是 regorafenib 和 pazopanib 在临床研究中疗效不足的原因。纳米晶化被认为是克服这一问题的有效方法之一。
