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David Gale, Caroline Sychterz, Ciara Rodgers, Sherry Wang, Tom Wilde, Anu Shilpa Krishnatry, Harma Ellens; Ocular and Systemic Pharmacokinetics of a PDE4 Inhibitor Following Topical Administration (Eyedrop) in Male Dutch-Belted Rabbits. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5060.
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To evaluate the ocular and systemic pharmacokinetics of a phosphodiesterase 4 (PDE4) inhibitor following topical eyedrop administration in male Dutch-Belted rabbits.
All studies were conducted according to the GSK Policy on the Care, Welfare and Treatment of Laboratory Animals after review by the GSK Institutional Animal Care and Use Committee and in compliance with the ARVO Statement on the Use of Animals in Ophthalmic and Visual Research. Male Dutch-Belted rabbits were topically dosed with a potent PDE4 inhibitor (GSK907188, IC50 <100pM) with either a 0.07 mg/mL or 7.6 mg/mL solution formulation. Plasma samples were collected to measure the systemic exposure of GSK907188. Ocular tissues were collected from post-mortem enucleated eyes. GSK907188 levels were quantitated in plasma and ocular tissue samples using an HPLC/MS/MS method. The predicted human systemic exposure was estimated from rabbit systemic exposure, clearance values and GastroPlusTM modeling.
GSK907188 levels in rabbit plasma, following topical administration of the 7.6 mg/mL formulation, were quantifiable out to 6hrs (6hr plasma levels = 0.40 ± 0.16 ng/mL). The rabbit plasma AUC(0-6hr) was 14.7 ± 3.50 ng*h/mL. The predicted human systemic exposure is 140-fold lower than the systemic exposure observed in rabbit. Ocular tissue levels were measured after topical administration of the 0.07mg/mL formulation. The highest GSK907188 levels were observed in the conjunctiva, where levels decreased from a Cmax of 50.5 ng/g tissue at 1hr to 0.48 ng/g at 24hr. GSK907188 concentrations in the cornea were low compared to the levels observed in the conjunctiva and remained relatively consistent throughout the study. Levels of GSK907188 in the lacrimal gland were low (<0.5 ng/g) but measureable out to 6 hr. Aqueous humor levels were below the limit of quantitation (0.1 ng/mL) for all samples, except the 1hr time point (0.12 ng/mL).
PDE4 inhibitors may be an important new class of molecules for inflammatory eye diseases. Preclinical pharmacokinetic studies, in-vitro studies and modeling can be utilized to provide an estimate of human systemic exposure, which is an important consideration with PDE4 inhibitors. For GSK907188, a formulation strength of >1 mg/mL may be required to generate efficacious concentrations in the cornea, conjunctiva and lacrimal gland.
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