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T. R. Johnson; Pharmacokinetics and Ocular Distribution of PF-04523655, an RTP801-Inhibiting siRNA, Following Intravitreal Administration in Rabbits. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2442.
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PF-04523655 is a chemically-modified small-interfering RNA (siRNA) designed to inhibit expression of the hypoxia-inducible gene, RTP801. It is currently in clinical development for the treatment of diabetic macular edema (DME) and neovascular age-related macular degeneration (AMD). This study evaluated the pharmacokinetics and ocular tissue distribution of PF-04523655 in rabbits following intravitreal administration.
A total of 12 Dutch-belted rabbits (n = 2/timepoint) received a single bilateral intravitreal injection of PF-04523655 at 2 mg/eye. At various time intervals over 10 days postdose, vitreous humor, retina, choroid, aqueous humor and plasma samples were collected, and PF-04523655 concentration was determined using a dual hybridization method. Pharmacokinetic parameters were determined from composite concentration-time data using noncompartmental methods.
Following a single intravitreal injection of PF-04523655, volume of distribution in vitreous humor (3.6 mL) was within 2- to 3-fold of the physiological vitreous humor volume in rabbits (~1.5 mL), and elimination t½ was 35 hours. PF-04523655 exposure was similar in vitreous humor and retina, with somewhat lower exposure observed in choroid. Exposure in aqueous humor was approximately 5-fold lower than vitreous humor. Elimination t½ of PF-04523655 from all ocular tissues was similar, with values ranging from 33 to 41 hours. Plasma exposure was approximately 10,000-fold lower than corresponding exposure in vitreous humor. Elimination t½ from plasma mirrored that of vitreous humor, suggesting that absorption of PF-04523655 into the systemic circulation from ocular tissues is the rate-limiting step in the overall pharmacokinetic profile following intravitreal administration.
Following intravitreal injection, PF-04523655 has a t½ in vitreous humor of 35 hours with minimal systemic exposure. PF-04523655 readily distributes into the retina and choroid, supporting its clinical development for DME and neovascular AMD.
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