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L. Cheng, A. Tammewar, K. Y. Hostetler, J. R. Beadle, I. Falkenstein, E. C. Barron, K. A. Aldern, W. R. Freeman; Pharmacokinetics and Physicochemical Properties of a Prototype Compound With a Crystalline Intravitreal Drug Delivery System; Octadecyloxyethyl Cyclic Cidofovir. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5003. doi: https://doi.org/.
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We previously reported a long-lasting slow release intravitreal crystalline drug delivery system (2004 Nov;45(11):4138-44.). In this study we characterized the intraocular distribution of octadecyloxyethyl cyclic cidofovir (ODE-cCDV) after intravitreal injection in rabbits using radiolabeled drug. We also determined the aqueous solubility of ODE-cCDV and correlated it with the observed pharmacokinetics.
Radiolabeled drug, ODE-2-[14C]-cCDV, was synthesized, and then dispersed in 5% dextrose (2.0 mg/ml). 24 New Zealand red rabbits received 50 µl intravitreal injection of the suspension (100 µg drug/eye). Vitreous, retina and choroidal tissues collected at 0.04, 1, 3, 7, 14, 21, 42, and 63 days were treated with liquid scintillation cocktail and counted to determine the concentration of ODE-cCDV. Aqueous solubility was determined using a shake-flask method and drug concentration at saturation was measured by UV spectrophotometry.
The pharmacokinetics demonstrated that crystalline ODE-cCDV had a vitreous half-life of 13.6 days, AUC of 1790 µg day/mg. The free drug in the retina had a half-life of 14 days, elimination rate of 0.05/day, AUC of 1757 µg day/mg. If IC90 against HCMV were 0.6 µg/ml, the duration of action would be 94 days. The free drug in the choroid had a half-life of 11 days, elimination rate of 0.06/day, AUC of 641 µg day/mg. If the IC90 were 0.6 µg/ml, the duration of action would be 60 days. The solubility of ODE-cCDV in water at 25 °C was found to be 0.16 mM.
ODE-cCDV has limited solubility but dissolves slowly after intravitreal injection to provide a long duration of action, up to 3 months. The released drug is absorbed into the retina and also reaches the choroids in therapeutic concentrations.
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