title: Intraocular safety and pharmacokinetics of hexadecyloxypropyl-cidofovir (HDP-CDV) as a long-lasting intravitreal antiviral drug.
abstract: OBJECTIVE
  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: Shiley Eye Center, University of California San Diego, La Jolla, California 92093-0946, USA.
authors: Haiyan
authors: H
authors: Wang
authors: Jay
authors: J
authors: Chhablani
authors: William R
authors: WR
authors: Freeman
authors: James R
authors: JR
authors: Beadle
authors: Karl Y
authors: KY
authors: Hostetler
authors: Kathrin
authors: K
authors: Hartmann
authors: Laura
authors: L
authors: Conner
authors: Kathy A
authors: KA
authors: Aldern
authors: Lindsey
authors: L
authors: Pearson
authors: Lingyun
authors: L
authors: Cheng
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D002924:Ciliary Body / Q000187:drug effects / Q000378:metabolism*; D017726:Cytomegalovirus Retinitis / Q000188:drug therapy* / Q000378:metabolism; D003596:Cytosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005500:Follow-Up Studies; D006868:Hydrolysis; D058449:Intravitreal Injections; D063065:Organophosphonates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011817:Rabbits; D012160:Retina / Q000187:drug effects / Q000378:metabolism*; D014822:Vitreous Body / Q000187:drug effects / Q000378:metabolism*
chemical_list: D003692:Delayed-Action Preparations; D063065:Organophosphonates; C525733:brincidofovir; D003596:Cytosine