Intraocular Safety and Pharmacokinetics of Hexadecyloxypropyl-Cidofovir (HDP-CDV) as a Long-lasting Intravitreal Antiviral Drug

Human cytomegalovirus (CMV) infection can cause sight-threatening retinitis in patients with acquired immune deficiency syndrome (AIDS). Even though highly active antiretroviral therapy (HAART) has lowered the incidence of CMV retinitis, some patients have manifested poor response to HAART, and some patients do not qualify for it.1,2 Currently, the clinical treatment of CMV retinitis includes systemic and local administration of antiviral medications, such as ganciclovir (GCV), foscarnet, and cidofovir (CDV), as well as surgical GCV implants. With the lengthened exposure of patients to the drugs in the systemic treatment modality, GCV and foscarnet-resistant cytomegalovirus are becoming a concern.3,4 Therefore, the development of CDV for intravitreal injection would be a helpful therapeutic alternative in patients with GCV and foscarnet-resistant CMV strains. Intravitreal injection of small molecules often requires frequent repeated injections, which increases the risk of devastating endophthalmitis. Frequent injections also affect the quality of the patient's life.1,2 Surgical intravitreal implants provide longer therapeutic duration but the side effects associated with surgery, such as vitreous hemorrhage and retinal detachment, are often sight-threatening complications.2 As a result, our efforts have been directed toward developing long-lasting intravitreal injectable drugs to circumvent these problems.5 We previously identified lipid derivatized drugs that work well against both viral infections and proliferative diseases of the eye. For viral infections, these include hexadecyloxypropyl-phospho-ganciclovir and hexadecyloxypropyl-cyclic cidofovir (HDP-cCDV) and for proliferative vitreoretinopathy, hexadecyloxypropyl 5-fluoro-2′-deoxyuridine 3′,5′ cyclic monophosphate.5,6 In particular, HDP-cCDV, a long-lasting crystalline lipid prodrug of CDV that we have reported previously,5 shows a longer intraocular therapeutic effect than CDV in the experimental HSV retinitis of rabbit eye. Subsequent confirmatory evaluation of ocular toxicity in guinea pig eyes demonstrated that a dose of 18 μg HDP-cCDV/eye (equivalent to 100 μg/eye in the rabbit eye) is safe.7 Although the experimental treatment demonstrated efficacy, the ocular pharmacokinetics of this crystalline formulation has not been well characterized because of its low water solubility and low free drug concentration in the vitreous. Most recently, we performed an intraocular pharmacokinetic study of octadecyloxyethylcyclic-[2-14C]cidofovir (ODE-cCDV), which is a crystalline prodrug similar to HDP-cCDV, except that it has one more carbon in the alkoxyalkyl moiety.8 Monitor drug levels in various tissues with scintillation counting showed that drug was detectable during the whole study period (9 weeks). Interestingly, the drug in vitreous demonstrated a two-compartment model with a very long vitreous elimination half-life of 25 days. How these crystalline lipid prodrugs work in a living eye to inhibit viral replication is not completely clear. After intravitreal injection, the drug forms a depot in the vitreous due to its limited water solubility. It is possible that small quantities of HDP-cCDV leave the drug depot and migrate into the retina where HDP-cCDV is converted to CDV through phospholipase C cleavage of HDP and hydrolysis of cCDV to CDV. Another possibility is that, in the vitreous, HDP-cCDV is slowly hydrolyzed to HDP-CDV which can aggregate to form micelles, which are then transported into retinal cells (Fig. 1). If the latter is the case, study of ocular pharmacokinetics of HDP-CDV would help to better understand the crystalline intravitreal drug delivery system. Figure 1. Proposed mechanism for sustained release of HDP-CDV from a crystalline depot of HDP-cCDV in the vitreous. In this study, we used 14C-labeled HDP-CDV to study the intraocular pharmacokinetics of this compound and attempted to detect its metabolites such as CDV, CDV monophosphate, and CDV diphosphate in retinal tissues.