Further Characterization of a Novel Intraocular Drug Delivery System using Crystalline 1- O-hexadecyloxypropyl-cyclic Cidofovir

Abstract

Abstract: : Purpose: We have previously reported a novel intraocular drug delivery system using 1-O-hexadecyloxypropyl-3-phospho-ganciclovir (HDP-P-GCV) as a prototype (IOVS 2002; 43(2): 515-21). We hypothesized that many biologically effective compounds could be modified to a crystalline lipid prodrug as we reported and be directly delivered into vitreous as a long-lasting, slow release system. The current study is to further demonstrate the safety and effectiveness of this new drug delivery system using commercially available cyclic cidofovir. Methods: Crystalline 1-O-hexadecyloxypropyl-cyclic cidofovir (HDP-cCDV) was synthesized by coupling 1-O-hexadecylpropanediol (HDP) to cyclic cidofovir. The crystalline compound was intravitreally injected into rabbit vitreous with 10, 55, 100, 550, or 1000 µg in 50 µl per eye. The toxicity and safety including intraocular pressure was evaluated with tonometry, ophthalmoscopy, electroretinography, and pathology. Vitreous drug levels were determined at intervals following injection of the highest non-toxic dose (100 µg/eye) using HPLC. Results: Intravitreal injections of doses of 100 µg/eye or lower revealed no toxicity, clear vitreous, and desirable drug depot ophthalmoscopically visible in the inferior vitreous cavity. HPLC analysis showed a vitreous HDP-cCDV level of 0.05 µM at 5 weeks and descending to 0.002 µM at 8 weeks after 100 µg/eye intravitreal injections. The concentration at week 5 post-injection (0.05 µM) was above the IC50 for HSV-1 (0.04 µM) and IC50 for CMV (0.0003 µM). The concentration at week 8 (0.002 µM) remained above the IC50 for CMV.Conclusions: This crystalline lipid prodrug intravitreal delivery could be a safe and effective approach to achieve a sustained therapeutic drug level in an eye, and crystalline HDP-cCDV could be an alternative to treat Herpes group virus retinitis, particularly CMV retinitis.

Keywords: pharmacology • drug toxicity/drug effects • vitreous