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Lisa Schopf, Elizabeth Enlow, Pawel Nowak, Winston Ong, James Bourassa, Kim Brazzell, Hongming Chen; Topical Delivery of a Novel Receptor Tyrosine Kinase Inhibitor (RTKi) via Mucus-Penetrating Particles. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2279.
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© 2017 Association for Research in Vision and Ophthalmology.
A new chemical entity was designed and synthesized to potently and selectively block VEGF signaling. The compound was formulated as a mucus-penetrating particle (MPP) eye drop and the ocular and systemic pharmacokinetics (PK) were evaluated following topical delivery to rabbits and mini-pigs. MPPs rapidly and uniformly coat and penetrate mucosal barriers, and have the potential to increase drug exposure to underlying tissues and improve topical ocular drug delivery.
K106 was synthesized and enzyme/cellular potency determined. Selectivity was evaluated with a 97-kinase panel and IC50s were calculated for KDR, EGFR, FGFR, and RET. PK profiling of topically administered K106 formulated as MPP was performed in rabbits. Efficacy was carried out in a rabbit model of vascular leakage. To evaluate drug delivery in larger species, PK profiling was performed in mini-pigs.
K106 has an enzymatic affinity of 0.30 +/- 0.08 nM and a cellular potency of 0.21 +/- 0.13 nM for KDR. K106 affinity for KDR over other targets EGFR, FGFR and RET were 733, 90, and 30-fold, respectively. After a single topical dose of 0.5% K106-MPP to rabbits, the drug concentrations, expressed as area under the curve calculated over 0-12hr, were 4270 (choroid), 474 (retina) and 9 nM*hr (plasma). After 5 days of topically dosing 0.5% K106 twice-a-day (BID) to rabbits, the tissue drug concentrations increased about 8-fold in the choroid and 2-fold in the retina while the plasma concentrations decreased 3-fold compared the PK profile after a single dose. A dose proportional decrease in drug levels in all compartments was observed after lowering the dose of K106 to 0.05% (5 days, BID). Furthermore, significantly reduced vascular leakage was observed in rabbits, suggesting that biologically active concentrations of the novel RTKi were delivered to the back of the eye following topical delivery of the MPP formulation. Lastly, PK profiling in the mini-pig revealed back of the eye ocular levels exceeding the cellular IC50 of KDR by 400-fold over the time course evaluated.
We have demonstrated in in vitro and animal models that K106 is a potent and selective inhibitor of the VEGF pathway, and can be formulated as an MPP. Also, preclinically we have verified that this novel topical RTKi reaches the back of the eye which could be a major breakthrough in providing a noninvasive means to treat retinal disease.
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