title: Assessing a novel depot delivery strategy for noninvasive administration of VEGF/PDGF RTK inhibitors for ocular neovascular disease.
abstract: OBJECTIVE
  Two noninvasive delivery strategies for VEGF/PDGF receptor tyrosine kinase inhibitors (RTKI) were explored that exploited uveal retention as a means for establishing an ocular drug depot: a single oral "loading" dose and topical administration.
  
  
  METHODS
  Melanin binding was confirmed by centrifugation and mass spectrometry. Ocular retention was examined in pigmented and albino rats. Ocular release kinetics were measured 3 to 28 days postdosing in pigmented rats. Microautoradiography was used to demonstrate retention of RTKI in the uveal tract. A uveal drug depot of pazopanib was created by a single oral dose prior to induction of laser choroidal neovascularization (CNV). Choroid/retinal pigmented epithelium (RPE) retention of a related RTKI with enhanced topical bioavailability, GW771806, was confirmed by bioanalytics, and its ability to regress CNV compared with pazopanib.
  
  
  RESULTS
  Pazopanib and GW771806 directly bound melanin and were retained within the uveal tract of pigmented rats for weeks following a single oral dose. Pazopanib was undetectable systemically following a single oral administration prior to CNV induction, and reduced CNV as well as twice daily dosing. Topical ocular delivery of GW771806 at 5 mg/mL led to high choroidal/RPE exposure and significantly regressed CNV lesions; 2 mg/mL prevented lesion progression.
  
  
  CONCLUSIONS
  Uveal retention of drugs such as pazopanib can be used to create a sustained-release depot. Topical GW771806 regressed CNV. These data indicate that topical or infrequent oral loading dose treatment with VEGF/PDGF RTKI retained in the choroid/RPE might allow noninvasive treatments for ocular neovascular disease.
authors: Department of Genetics, University College London Institute of Ophthalmology, London, United Kingdom.
authors: Scott J
authors: SJ
authors: Robbie
authors: Peter
authors: P
authors: Lundh von Leithner
authors: Meihua
authors: M
authors: Ju
authors: Clemens A
authors: CA
authors: Lange
authors: Andrew G
authors: AG
authors: King
authors: Peter
authors: P
authors: Adamson
authors: Dennis
authors: D
authors: Lee
authors: Caroline
authors: C
authors: Sychterz
authors: Pete
authors: P
authors: Coffey
authors: Yin-Shan
authors: YS
authors: Ng
authors: James W
authors: JW
authors: Bainbridge
authors: David T
authors: DT
authors: Shima
mesh_terms: D000284:Administration, Oral; D000287:Administration, Topical; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000818:Animals; D001345:Autoradiography; D020256:Choroidal Neovascularization / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D016503:Drug Delivery Systems; D005260:Female; D005451:Fluorescein Angiography; D006207:Half-Life; D007191:Indazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008543:Melanins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D011743:Pyrimidines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013450:Sulfones / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014602:Uvea / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; C580765:GW771806; D007191:Indazoles; D008543:Melanins; D011743:Pyrimidines; D013449:Sulfonamides; D013450:Sulfones; C516667:pazopanib; C099852:PDGF receptor tyrosine kinase; D017479:Receptors, Platelet-Derived Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1