Intraocular safety and pharmacokinetics of hexadecyloxypropyl-cidofovir (HDP-CDV) as a long-lasting intravitreal antiviral drug.

Abstract

PURPOSE:

To evaluate the intraocular safety and pharmacokinetics of hexadecyloxypropyl-cidofovir (HDP-CDV), the hydrolysis product of HDP-cyclic-CDV, a long-lasting intravitreal cidofovir prodrug for cytomegalovirus (CMV) retinitis.

METHODS:

HDP-cyclic-CDV was suspended in phosphate-buffered saline (PBS) at 37°C and formation of HDP-CDV was monitored by high-performance liquid chromatography (HPLC) analysis for 30 weeks. The safety and pharmacokinetics of HDP-CDV intravitreal injections were studied using New Zealand Red rabbits and (14)C labeled HDP-CDV. Ocular tissues from five time points (1, 3, 7, 14, and 35 days) were analyzed by scintillation counting and HPLC to characterize the pharmacokinetics.

RESULTS:

During the hydrolysis study, approximately 35% of the HDP-cyclic-CDV was converted to HDP-CDV. Evaluation of safety found no toxicity after intravitreal injection of HDP-CDV up to 28 μg/eye. Intravitreal pharmacokinetics of HDP-CDV in the retina, choroid, and vitreous followed a two-phase elimination process and elimination half-lives of 8.4 days (retina), 6.9 days (choroid), and 6.2 days (vitreous). In the retina, cidofovir and an unknown metabolite were detected in the first 2 weeks, and the maximum metabolite concentrations were present 48 hours after the maximum HDP-CDV concentration.

CONCLUSIONS:

HDP-cyclic CDV, under simulated physiologic conditions, slowly converts to HDP-CDV, another potent anti-CMV prodrug that may be taken up by retinal cells and metabolized further to the active antiviral metabolite, cidofovir diphosphate. Taken together, these observations help to explain the ability of a single intravitreal dose of HDP-cyclic-CDV to prevent viral retinitis for up to 68 days in a rabbit model.

• Authors: Haiyan Wang, Jay Chhablani, William R Freeman, James R Beadle, Karl Y Hostetler, Kathrin Hartmann, Laura Conner, Kathy A Aldern, Lindsey Pearson, Lingyun Cheng
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 52 Issue 13 Pg. 9391-6 (Dec 09 2011) ISSN: 1552-5783 [Electronic] United States
• PMID: 22058340 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Delayed-Action Preparations
• Organophosphonates
• brincidofovir
• Cytosine

Topics

• Animals
• Chromatography, High Pressure Liquid
• Ciliary Body (drug effects, metabolism)
• Cytomegalovirus Retinitis (drug therapy, metabolism)
• Cytosine (administration & dosage, analogs & derivatives, pharmacokinetics)
• Delayed-Action Preparations
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Follow-Up Studies
• Hydrolysis
• Intravitreal Injections
• Organophosphonates (administration & dosage, pharmacokinetics)
• Rabbits
• Retina (drug effects, metabolism)
• Vitreous Body (drug effects, metabolism)