Ocular Drug Distribution of TG100801 (VEGFR2 Inhibitor) and TG100572 (VEGFR2, PDGFR, Src Inhibitor) Following Topical Instillation in Multiple Preclinical Species

Abstract

Purpose: : To evaluate ocular pharmacokinetics of TG100801 (VEGFR2 inhibitor) and its metabolite (TG100572, a potent multi–targeted Src/VEGFR2/PDGFR kinase inhibitor) following topical instillation in multiple preclinical species

Methods: : TG100801 or TG100572 was administered as eye drops (10 – 50 µL/eye) to mice, rabbit, dog or mini–pig. Animals were sacrificed at various time–points and ocular tissues and plasma samples were collected. For rabbit study, both the left and right dissected ocular tissues from each animal were combined for analysis. In dogs and mini–pigs, dissected tissues from each eye were analyzed individually. In mice, ocular tissues from 2–4 eyes were combined and analyzed. Tissues were homogenized with RIPA buffer and analytes were extracted in acetonitrile. TG100801 and TG100572 were quantitated using an LC/MS/MS assay and concentrations were normalized using tissue weight. Data was analyzed using WINNONLIN.

Results: : TG100801 is primarily converted to TG100572 by ocular esterase enzymes following topical delivery. Both TG100801 and TG100572 were shown to achieve concentrations exceeding those needed for inhibition of target tyrosine kinases in back–of–the–eye tissues in multiple preclinical species (mini–pig, rabbit and dog). Ocular pharmacokinetics of TG100801/TG100572 (T1/2 > 7 h) suggests that once or twice a daily topical instillation should be sufficient to maintain exposure in target tissues above therapeutic concentration levels. Both TG100572 and TG100801 demonstrate high systemic clearance in vivo. Additionally, systemic exposure to TG100572 and TG100801 following topical delivery of TG100801 was lower than the limit of quantitation (1–3 ng/mL), suggesting minimal potential for systemic side effects.

Conclusions: : TG100801 and its active metabolite (TG100572) show high ocular penetrance following topical instillation to the back–of–the–eye tissues in multiple species. Lack of systemic and aqueous humor exposure and high conjunctival/scleral exposure suggests that the most probable pathway of delivery to the back–of–the–eye is via the non–corneal pathway.

Keywords: choroid • retina • age-related macular degeneration