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Lingyun Cheng, Haiyuan Wang, Jay Chhablani, James Beadle, Kathrin Hartmann, Laura Conner, Kathy Aldern, Lindsey Pearson, Karl Hostetler, Willianm Freeman; Intraocular Pharmacokinetics Of Hexadecyloxypropyl Cidofovir (hdp-cdv) As An Intravitreal Long-lasting Antiviral Drug For CMV Retinitis. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2066.
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To investigate the distribution and clearance kinetics of intravitreal HDP-CDV.
Three doses, each with three rabbits, were used to evaluate the safety of intravitreal HDP-CDV to determine the ideal dose for an intraocular pharmacokinetic study. Pharmacokinetics of intravitreal HDP-CDV at 28 micrograms injected per eye was studied using 20 rabbits with 5 time points. The safety was evaluated by clinical exam, electroretinography, and histology. Pharmacokinetics was studied by modeling of the tissue drug concentration-time profile using scintillation counting as well as HPLC.
All three concentrations tested (2.8 µg/ml, 8.7 µg/ml, 28 µg/ml) did not show ocular toxicity. The mean IOPs were 15.4, 16.5, 16.1, and 15.4 mmHg for 2.8µg, 28µg, dextrose, and 9µg dose respectively (p=0.76). ERG b wave amplitude was 83, 102, 108, and 91 µV for 28µg, 2.8µg, 9µg, and dextrose respectively (p=0.296). TUNEL staining of the histology section from the highest dose did not show evidence of apoptosis. The pharmacokinetic study revealed that HDP-CDV can be detected in retina, ciliary body, and vitreous through the last time point (5 weeks) following a single intravitreal injection of 28 microgram. The drug elimination half-life was 6 days for the vitreous, 8 days for the retina, and 11 days for the ciliary body. Tmax was 3 days for the ciliary body, and 1 day for both the vitreous and retina. Cmax was 4.6 µg/ml for the ciliary body, 80.4 µg/ml for the retina, and 3.8 µg/ml for the vitreous. The retina had the most drug exposure with AUClast of 318 µg•day/ml and followed by the AUClast of 66 µg•day/ml for the ciliary body and the AUClast of 18 µg•day/ml for the vitreous.
Crystalline lipid prodrug, HDP-CDV, was long-lasting in vitreous, ciliary body, and retina following a single intravitreal injection. HDP-CDV accumulates in both the ciliary body and retina. Retina had the most total drug exposure, which is ideal for treatment of retinal diseases such as CMV retinitis.
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