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Yubin Qiu, Siyuan Shen, Elizabeth S Fassbender, Amber Woolfenden, Debby Long, Ron Newton, Erik Meredith, Bruce D Jaffee, Stephen H Poor, Ophthalmology, Novartis Institutes for BioMedical Research, Inc.; Weekly oral delivery of a vascular endothelial growth factor receptor (VEGFR) inhibitor compound optimized for ocular exposure improves safety and maintains efficacy compared to daily dosing. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):151.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate different dosing frequency regimens of VEGFR inhibitors in a rat laser-induced choroidal neovascularization (CNV) model.
Compound A (DB-83-LM4) and B (UF-61-QB443) inhibit VEGFR-2 in a biochemical assay with IC50 of 41 nM and 8 nM respectively. PK of A and B were investigated after single oral doses in Brown Norway rats (n = 2 rats/ 4 ocular samples per time point, 10 time points over 0-96 hrs). Oral dose-response studies of A and B were performed in a rat laser-induced CNV assay, dose range was 0.3 - 30 mg/kg/day. Laser was applied on day 0, CNV area measured between 11-14 days later by i.v. injection of a vascular label, flat mount imaging and analysis of CNV area by morphometric analysis. There were 4 laser pulses per eye, 10 rats per group yielding 80 data points per group. ED50 and ED90 curves were generated from 5 - 10 studies per compound. In other experiments, rats were pre-dosed daily for 2 weeks before laser with compound or vehicle in addition to daily dosing after laser to determine if pre-dosing improved efficacy. To investigate dose frequency-efficacy relationships, B was dosed at 3, 10, or 30 mg/kg every 1, 2, 3, 4, or 6 days starting on day 0. In addition, A and B were dosed weekly at ~ daily ED80 doses. Toxicology studies were performed for B with either daily or weekly dosing in Wistar rats.
Compounds A and B exhibited prolonged exposure in the RPE-choroid complex, with minimal plasma exposure after 24 hrs. However, A had retinal exposure only to 24 hrs while B had prolonged retinal exposure out to 96 hrs. The daily ED50 and ED90 of A were 0.65 and 3.4 mg/kg while for B it was 3.0 and 14.3 mg/kg. Predosing of either compound offered similar efficacy to dosing in the standard format. Compound B dosed at 10 or 30 mg/kg was equally efficacious dosed every 1, 2, 3, 4, or 6 days. In contrast, at 3 mg/kg, B lost efficacy with less than daily dosing. Weekly or daily dosing of A at 2.5 mg/kg inhibited CNV by 25 and 90%, respectively. However, dosing B at 10 mg/kg daily or weekly demonstrated similar efficacy (87% vs 72%). Toxicology studies with weekly vs daily dosing improved the therapeutic index of B by ~ 10 fold.
Weekly oral doses of VEGFR inhibitor B had similar efficacy as and less toxicity than daily dosing of the same compound.
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