Intraocular Pharmacokinetics of a Crystalline Lipid Prodrug, Octadecyloxyethyl-Cyclic-Cidofovir, for Cytomegalovirus Retinitis

Abstract

Purpose: To evaluate the intraocular pharmacokinetics of octadecyloxyethyl-cyclic-cidofovir (ODE-cCDV) after intravitreal injection into rabbit eyes. Methods: Twenty-seven New Zealand red rabbits (27 eyes) received intravitreal injections of 14 C-labeled ODEcCDV (100 mg drug suspended in 5% dextrose), and ocular tissues were collected from 3 rabbits at each predetermined time point (1 h, 1 day, 3 days, 1 week, 2 weeks, 3 weeks, 5 weeks, and 9 weeks) after the injection. The eye globes were enucleated, and the vitreous, retina, and choroids were separated and harvested into preweighed scintillation vials. Levels of ODE-cCDV were measured by counting in a liquid scintillation counter, and pharmacokinetic (PK) parameters were determined. In addition, 3 eyes of 3 animals were used for autoradiography study at day 1, week 3, and week 6. Results: ODE-cCDV in vitreous as a whole followed a 2-phase first-order elimination, whereas ODE-cCDV in retina and choroid manifested a nearly steady state during the first 3 weeks and then followed a first-order elimination with the apparent elimination half-life of 10.1 and 7.2 days. For vitreous, apparent elimination halflife was 25 days. However, the drug mean residence time was much longer in retina (17.6 days) and choroid (19.6 days) than that in the vitreous (11.6 days). The drug exposure to the retina [area under the curve (AUC) ¼ 1120837.1 ng Á day/mL] was greater than the exposure to the vitreous (AUC ¼ 958645.8 ng Á day/mL) and the choroid (AUC ¼ 415407.47). Conclusion: A crystalline lipid prodrug, ODE-cCDV, has longer vitreous half-life than that in other ocular tissues due to its solid drug depot formation in vitreous. Over time, dissolved free ODE-cCDV from drug depot feeds and accumulates in the retina.

Transporter-Targeted Lipid Prodrugs of Cyclic Cidofovir: A Potential Approach for the Treatment of Cytomegalovirus Retinitis

“…Retinal pigment epithelium (RPE) cells display high membrane lipophilicity and tight junctions. So far, different approaches have been employed to enhance permeability of CDF such as lipid prodrugs 14 or transporter-targeted prodrugs of cCDF 1 . However, individually, these approaches have exhibited limited advantages.…”

“…In order to resolve such problems, researchers have synthesized lipid conjugates of cCDF (octadecyloxyethyl–cCDF) for intraocular injection to improve its vitreal half-life, bioavailability, and antiviral efficacy. 14 However, the major limitation of lipid conjugates is the higher retention in lipid bilayer of plasma membrane and inability to translocate into the cytoplasm due to which it is not effective in treating deeper tissue infection such as CMV retinitis. Moreover, the low aqueous solubility of lipid prodrugs can further restrict the application of this approach.…”

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

“…In previous studies, we showed that intravitreal injection of crystalline lipid prodrugs of small molecules, such as antiviral and antiproliferative nucleosides can be an effective strategy for the sustained delivery of drugs to the posterior segments of the eye. 5,6,8 In a recent study, we found that hexadecyloxypropyl cytarabine cyclic 3Ј,5Ј-monophosphate can be hydrolyzed to its noncyclic form, hexadecyloxypropyl-phosphocytarabine, which is water soluble and forms micelles (Cheng L, et al, unpublished data, 2011). We hypothesized that the cyclic form of HDP-cCDV could also be hydrolyzed in vitreous fluid, converting a significant portion of HDP-cCDV into HDP-CDV before reaching the retina.…”

“…After injection, four rabbits at each time point (days 1, 3, 7, and 14 and week 5) were euthanized and the aqueous humor, iris, ciliary body, vitreous, retina, and choroid were sampled after eye globe enucleation, as we previously described. 8,9 For retina and ciliary body, the samples were divided into two, one for total radioactivity counting with scintillation and the other for metabolite study by HPLC/MS. The vials were kept at Ϫ80°C until further analysis.…”

“…Most recently, we performed an intraocular pharmacokinetic study of octadecyloxyethylcyclic-[2-14 C]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.…”