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Rozemarijn S Verhoeven, RiLee Robeson, Andres Garcia, Brian C Gilger, David Culp, Craig B Struble, Lee Hamm, Thomas Grizzle, Tomas Navratil, Rhett M Schiffman; A 6-Week Ocular Pharmacokinetic Study of ENV905 (difluprednate) Intracameral Implant or Durezol in the Albino Rabbit. Invest. Ophthalmol. Vis. Sci. 2016;57(12):5711.
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© ARVO (1962-2015); The Authors (2016-present)
To assess the ocular and systemic pharmacokinetics (PK) of intracameral ENV905 compared with topical Durezol in the albino rabbit. ENV905 is being developed as a treatment for inflammation and pain associated with ocular surgery.
Male NZW rabbits (2/group/terminal time point) were administered a single bilateral intracameral administration of ENV905 (40ug/eye), or Durezol administered according to the clinical standard of care (Days 1-14 QID, Days 15-21 BID, Days 22-28 QD, 1925ug/eye), and were followed for up to 42 days. Durezol samples were obtained 30 minutes post-dose. Ocular matrixes were analyzed using LC-MS/MS for difluprednate (DFBA, parent) and desacetyl difluprednate (DFB, metabolite) and plasma was analyzed for DFB only. Data was assessed for non-compartmental PK parameters using WinNonlin.
Exposure to DFB was generally consistent in each matrix over the 28-day Durezol dosing period at 30 minutes post-dose (AUC = cornea>trabecular meshwork (TM)>conjunctiva>iris/ciliary body (ICB)> aqueous humor (AH)>retina>plasma) and samples were mostly BLQ by Day 42. For ENV905, DFB peaked on Day 1 (AUC = ICB>cornea>TM>AH>conjunctiva> retina>plasma), had markedly decreased in concentration in all matrixes by Day 7, and was BLQ in all samples by Day 21. When ENV905 and Durezol were compared, DFB Cmax was increased for ENV905; AUC was considerably higher for Durezol in cornea and TM, and was higher in the other matrixes with the exception of ICB which was higher for ENV905.
Durezol administration resulted in consistent exposure to DFB in plasma and ocular samples over 28 days, with the greatest exposure over time in cornea and TM. DFB concentrations for ENV905 peaked on Day 1 at higher concentrations than Durezol, but dissipated in a tapering manner over 14 days, with the greatest exposure over time in the ICB. There was no detectable exposure to the TM after day 14 which may reduce the incidence of steroid responsive IOP spikes following cataract surgery. Administration of ENV905 at the site of inflammation following cataract surgery allows for significant dose sparing, targeted distribution to the tissues of interest, and decreased cumulative exposure to the corticosteroid.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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