Species differences in ocular pharmacokinetics and pharmacological activities of regorafenib and pazopanib eye‐drops among rats, rabbits and monkeys

Abstract

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.

A novel method of screening combinations of angiostatics identifies bevacizumab and temsirolimus as synergistic inhibitors of glioma-induced angiogenesis

“…Some of the observed doses of no effect are likely to be higher than what might be expected for human clinical use due to lower affinity for interacting with either the chick vasculature or to factors released by the rat 9L tumors. Indeed, bevacizumab has been shown to have 5-fold lower affinity for rat VEGF [ 51 ] and Pazopanib has demonstrated slightly lower activity in rat corneal models [ 52 ], but both are commonly used in rat models of angiogenesis. Sunitinib and temsirolimus have also been shown to successfully inhibit tumor angiogenesis in rat models of glioma and colorectal cancers [ 53 , 54 ] although we could not find concrete information on relative affinities for rat versus human for either drug.…”

Effects of Regorafenib, a Multi-Kinase Inhibitor, on Conjunctival Scarring in a Canine Filtration Surgery Model in Comparison with Mitomycin-C

“…MMC also reduces the secretion of collagen [35] and induces apoptosis in what appears to be a c-Jun N-terminal kinase 1 (NJK1) signaling-dependent mechanism [36]. Unfortunately, the effect of regorafenib on bleb formation has not been reported in detail, although regorafenib eye drops have been shown to significantly reduce choroidal neovascularization in a rat model through inhibition of VEGFR-2 [37]. Regorafenib also inhibits growth factors (such as PDGF, VEGF, and FGF) and cytokines (such as TGF-β) and suppresses the proliferation of fibroblasts.…”

The Emerging Role of Topical Ocular Drugs to Target the Posterior Eye

“…Laboratory animals are the major tools for the preclinical evaluation of new drug molecules including topical formulations. These tools were used to demonstrate promising efficacy and good accessibility to the fundus of rodents of numerous topical small molecular drugs, such as TG100801, pazopanib, acrizanib, regorafenib, and OT-551 [16,[184][185][186][187][188][189][190][191]. However, these drug molecules failed to achieve similar efficacy and therapeutic concentration in patients.…”

“…Both drug molecules achieved desirable therapeutic concentrations in rat fundus and inhibited CNV in a rat model. However, similar pharmacokinetics and efficacy results were not achieved in rabbit and monkey eyes [ 184 ]. A phase II clinical trial of regorafenib eye drops for neovascular age-related macular degeneration (AMD) was terminated because of inferior efficacy compared with current nAMD therapy, presumably as a result of insufficient drug exposure to the posterior segment [ 185 ].…”