Abstract
Purpose :
Cytokines such as epidermal growth factor, fibroblast growth factor-2, nerve growth factor, platelet derived growth factor, transforming growth factor-β and vascular endothelial growth factor are thought to play a role in the formation of pterygium. We hypothesized that inhibition of one or more of these cytokines by tyrosine kinase inhibitors (TKIs) could be used to treat pterygium. We tested our hypothesis using a rabbit corneal neovascularization model.
Methods :
Microsuspensions (0.3%) of three TKIs (nintedanib, axitinib, and sorafenib) were tested in a rabbit corneal neovascularization (NV) model to determine their ability to inhibit NV following three times daily (TID) ocular dosing for 14 days (N=6 eyes/group). AG-86893 (0.1 – 1%) was developed and tested to assess its efficacy following TID dosing for 7 days after induction of NV. Furthermore, the ocular pharmacokinetics of AG-86893 (0.1%) in rabbits were determined after a single topical eye drop (N = 4 eyes/group) and compared to that of a solution formulation (0.1%). Pharmacokinetic parameters (Cmax, Tmax, AUC, T1/2, where applicable), were determined in key ocular tissues using Phoenix WinNonLin v. 7.0.
Results :
Of the TKIs tested, nintedanib and axitinib showed significant inhibition on blood vessel growth, blood vessel length, and area of NV on day 7 compared to vehicle (p<0.0001). Surprisingly, sorafenib had little effect. AG-86893 equally inhibited NV at all 3 doses tested, indicating that the maximal inhibitory effect was reached at 0.1% TID. All 3 doses showed significant inhibition compared to vehicle (p<0.0006). AG-86893 showed higher exposure and longer ocular tissue half-lives compared to a solution formulation.
Conclusions :
Our results show that TKIs have the potential to treat pterygium. AG-86893 has potential for treating pterygium with once daily ocular dosing.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.