April 2010
Volume 51, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2010
Pharmacokinetics and Ocular Distribution of PF-04523655, an RTP801-Inhibiting siRNA, Following Intravitreal Administration in Rabbits
Author Affiliations & Notes
  • T. R. Johnson
    Pharmacokinetics, Dynamics & Metabolism, Pfizer Global Research & Development, San Diego, California
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 2442. doi:
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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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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : 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.

Methods: : 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.

Results: : 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.

Conclusions: : 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.

Keywords: vitreous • age-related macular degeneration • diabetic retinopathy 
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