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Clara Andonian; Ocular and Systemic Pharmacokinetics of GW559090, an Alpha-4 Integrin Antagonist, in Mouse, Rabbit and Dog Following Topical Administration. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4449.
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© ARVO (1962-2015); The Authors (2016-present)
To evaluate the ocular and systemic pharmacokinetics of a high-affinity α4β1 integrin antagonist (Kd=0.19 nM, MW = 596.67) in mouse, rabbit and dog following eye drop administration and to estimate the likely systemic exposure in humans.
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. Female C57BL/6N mice (2 mL), male Dutch-Belted rabbits (30 mL) and male Beagle dogs (30 mL) were topically dosed with a 30 mg/mL solution of GW559090. Plasma or blood samples were collected to measure the systemic exposure of GW559090. Ocular tissues were collected only from enucleated rabbit eyes at necropsy. GW559090 levels were quantitated in all samples using an UHPLC/MS/MS method.
In rabbit eye GW559090 levels were 2210 ng/g to 282 ng/g and 1100 ng/g to 266 ng/g from 0.5hr to 6hr post-dose for bulbar conjunctiva and cornea, respectively. GW559090 concentrations were 28.7 ng/mL and 68.6 ng/g in the aqueous humor and iris/ciliary body at 6hr post-dose, respectively. Circulating levels of GW559090 were generally quantifiable (2-27 ng/ml) up to 6 hours in rabbits and dogs and up to 1 hour in mice with maximum exposure of 14-124 ng/ml at Tmax ~0.083-0.25hr. AUC(0-t) values were 44.1 ng*h/mL, 31.5 ng*h/mL and 16.0 ng*h/mL in mouse, rabbit and dog, respectively. These systemic levels were used to estimate the projected human systemic exposure following eyedrop administration, by allometric scaling. The estimated human systemic exposure is 6.4ng*hr/mL, which is low.
GW559090 levels observed in the rabbit cornea and conjunctiva following eyedrop administrations were high. Significantly lower levels were observed in the plasma or blood of preclinical species studied. Thus, target exposure will be maximized while systemic exposure in humans will be minimized. Preclinical pharmacokinetic studies with GW559090 have been utilized to provide an estimate of target tissue exposure and human systemic exposure along with an understanding of ocular drug distribution. Topically administered α4β1 integrin antagonists may be an important new class of molecules for inflammatory eye diseases.
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