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L David Waterbury; An Alternative Method of Providing Effective Drug Concentrations in the Posterior Segment as Demonstrated in a Canine Pharmacokinetic Model. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2225.
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The direct injection of drugs into vitreous is a commonly described method of providing therapeutic drug concentrations to the posterior segment. An alternative method for achieving this objective was evaluated using a canine pharmacokinetic (PK) model.This PK model determines whether effective drug concentrations in the posterior segment can be obtained direct infusion into the aqueous humor along with their calculated duration of activity.
A formulation of phenylephrine and ketorolac injection 1%/0.3% (Omidria®) was administered after dilution in irrigation solution (4 mL in 500 mL) to 20 canines during lens replacement surgery. The aqueous humor was replaced by this solution. Ketorolac concentrations were determined by LC/MS in aqueous, cornea, conjunctiva, iris-ciliary body, vitreous, retina, choroid, retinal pigment epithelium, sclera, and lens capsule from 4 dogs per time point (0, 2, 6, 8 and 10 hours post-surgery). Concentration levels for tissues and time points were converted to log10 values, and linear coefficient values determined along with ‘best fit’ equations for each tissue.
The use of an irrigation solution containing phenylephrine and ketorolac provided therapeutic concentrations in the anterior segment. This method of administration unexpectedly provided therapeutic levels in the posterior segment extending for 10 hours by direct analysis, and up to 24 hours by calculations derived from a linear regression analysis. By calculating using the best fit linear regression analysis, levels of ketorolac in posterior tissues were sufficient to inhibit cyclooxygenase I (COX-1) up to 24 hours after administration. At 0-10 hours directly determined and calculated values at 20 hours post dose, concentrations were 8.2, 28.2, and 8.3 ng/ml for retina, vitreous, and posterior sclera respectively. All values (0-20 hours) were in excess of what is required for 50% inhibition of COX-1 (5.11 ng/ml) obtained from human recombinant COX-1.
Dosing by intracameral administration provides therapeutic concentrations to both anterior and posterior ocular tissues unlike topical dosing. This procedure in patients undergoing cataract surgery avoids the potential hazards of intravitreal injections, and insures adequate therapeutic concentrations in both the anterior and posterior segments for up to 20 hours after the procedure.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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