In the previous report, we first described this novel intraocular drug-delivery system using HDP-P-GCV as a prototype.
2 We reasoned that the hexadecyloxypropanol moiety could be coupled to many nucleoside phosphates or phosphonates to form solid hydrophobic crystals that slowly dissolve in water. The dissolved molecules enter the cells and are cleaved intracellularly by phospholipase C into hexadecyloxypropanol and the parent drug.
9 In the present study, we used the same concept and technique to synthesize an ether lipid ester of cyclic cidofovir, HDP-cCDV. Intravitreal injection of 100 μg or lower doses of HDP-cCDV crystals provided an ideal drug depot that floated in the inferior vitreous cavity without disturbing the visual axis. The vitreous elsewhere was clear and no toxicity was found in the eyes with 100 μg or lower doses. Local toxicity with higher doses was caused by the contact of drug depot with retina or lens, which was similar to the local retinal toxicity caused by intravitreal high-dose HDP-P-GCV.
2 The higher dose forms a larger drug depot in the vitreous, which tends to contact intraocular tissues and cause toxicity. An IOP decrease associated with intravitreal injection of CDV was not observed in the eyes that received 100-μg or lower doses in the present study. The eyes with higher doses showed a mild decrease in IOP at the last time point (8.7 ± 2.1 vs. 11.3 ± 2.3 mm Hg,
P = 0.01). However, no hypotony was found. Hypotony (IOP of 5 mm Hg or lower with associated retinal edema) is a well-known complication after local or systemic cidofovir administration.
10 11 The absence of hypotony may be because cyclic CDV and HDP-cCDV are not picked up avidly by organic anion transporters in the ciliary body. Intravitreal pharmacokinetics showed that HDP-cCDV was still detectable at week 10 after a single intravitreal injection of 100 μg per eye. The estimated vitreous half-life for HDP-cCDV was 6.3 days, which favorably compares to 20 hours for CDV or 10 hours for cCDV.
12 The detected concentration at week 8 was 0.002 μM, which is above the IC
50 for CMV. In this study, we did not detect HDP-cCDV in the retina, which could be due to low sensitivity of HPLC and fast conversion of HDP-cCDV into cCDV then into CDV by cellular phosphohydrolases. Using HDP-P-GCV, we have shown that the prodrug may be metabolized by participation of vitreous cells. There was little parent drug detectable when prodrug was incubated with a heat-inactivated vitreous sample, but conversion was detected readily by native vitreous that contains cells.
9 It has been known that CDV is phosphorylated to cidofovir diphosphate, the active form of cidofovir that has a long intracellular half-life.
13 Indeed, the pretreatment studies indicated at least 100 days of pharmacologic effect against HSV-1 infection of the rabbit retina. In the current studies, retinitis was graded in an unmasked manner. It could lead to bias if retinitis severity were similar to that in the treatment study. Therefore, we performed further objective analysis of retinal thickness from the pathologic examination for the treatment groups to confirm the findings. In the pretreatment studies, the severity of retinitis among the three groups was so obvious that it is unlikely that unmasked grading influenced the results.