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J.A. Ezzell, W.M. Peterson, C.S. Crean, J.L. Vittitow; Ocular Pharmacokinetics in Aqueous and Vitreous Humor of a Single Intravitreal Injection of Denufosol Tetrasodium (INS37217) in Dutch Belted Rabbits . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5697.
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Previous work has demonstrated that intravitreous injection of denufosol tetrasodium (INS37217) activates P2Y2 receptors at the apical (retinal–facing) membrane of the RPE and stimulates subretinal fluid reabsorption in animal models of retinal detachment. INS37217 is currently under clinical investigation for the treatment of non–diabetic macular edema. The objective of the present study is to determine the aqueous and vitreous humor pharmacokinetics (PK) of INS37217 following a single intravitreous injection.
A single 50µl intravitreous injection of INS37217 (121 µg) was administered bilaterally to 14 anesthetized Dutch Belted rabbits. The concentration of INS32717 in aqueous humor, vitreous humor, and epiretinal fluid (i.e., the aqueous interface separating gelatinous vitreous and retina) was assessed at ∼2 min, 30 min, 1, 2, 4, 8 and 16 hr post–injection (2 rabbits/4 eyes per time point). Quantitative bioanalysis of INS37217 was carried out using a Sciex 4000 LC–MS/MS system. The INS37217 range of detection for all matrices of was 25–20,000 ng/ml. Non–compartmental PK parameters were determined from the group mean data on each of the matrices using WinNonlin software.
INS37217 was above the limit of detection in aqueous humor out to 4 hr post–injection and above the limit of detection in vitreous humor and epiretinal fluid at all time points studied. Based on the peak concentrations of INS37217 in the three fluid compartments at 30 min post–injection, ∼100% of the initial dose was accounted for. However, by 16 hr post–injection less than 5% of the initial dose of INS37217 was still detected. The concentrations of INS37217 at 16 hr post–injection in vitreous humor and epiretinal fluid were 3.7µM and 2.7µM, respectively. Non–compartmental analysis determined a half–life for INS37217 of 2.6 hr in the vitreous humor, 3.5 hr in the epiretinal fluid and 1.2 hr in the aqueous humor.
Based on PK analysis of vitreous humor, aqueous humor, and epiretinal fluid, >95% of intravitreously injected INS37217 was cleared by 16 hr post–injection. The concentration of INS37217 in retina and subretinal space following intravitreous injection is not known. Based on the known pharmacology of this molecule with the P2Y2 receptor in RPE (EC50 of 1–5µM), these PK results suggest that the duration of action of INS37217 at this dose in rabbit is maintained up to the last time point studied. If clearance is consistent between human and rabbit, we speculate that the current clinical trial doses of INS37217 (60, 120, and 240 µg) are effective for 12–24 hr post–dosing.
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