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Christopher A. Paterson, Philippe Daull, Grégory Lambert, Laura Rabinovich, Jean-Sébastien Garrigue; The Lipophilic Prodrug Dexamethasone Palmitate, a Safe Alternative to Corticoid for the Treatment of Diabetic Macular Edema. Invest. Ophthalmol. Vis. Sci. 2011;52(14):448.
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The aim of the present study was to characterize the safety profile of oil-in-water emulsions of dexamethasone palmitate (DXP) in preclinical animal models.
Intravitreal (IVT) injections were performed with various doses of DXP oil-in-water emulsions either in rabbits, cats or minipigs. The highest DXP doses injected were 2600µg in both rabbits and minipigs. Ocular observations include slit lamp biomicroscopy, indirect opththalmoscopy and tonometry; performed either pretest and in week 2, 4, 6, and 8 in rabbits, or pretest and in week 1, 2, 4, 9, 18, 25, 31, 38 in minipigs. Blood samples were collected to characterize the systemic absorption of DXP and dexamethasone (DXM). At the end of the experimental period ocular (rabbits and minipigs) and general organs (minipigs) histopathology was performed. A validated cat model of DXM-induced elevated intraocular pressure (IOP) was used to assess the ocular hypertensive impact of an IVT injection of DXP oil-in-water emulsion (160 µg DXP).
Neither macroscopic nor microscopic ocular findings were observed in the rabbit at a dose as high as 1280 µg DXP. Plasma levels of DXM and DXP were very low, close to the LOQ (0.5 ng/ml) at days 15 and 29 post IVT injection in rabbits. The data confirmed that DXP emulsions are very well tolerated with a NOAEL at 1280 µg DXP. In minipigs the NOSEL was established at 2600 µg DXP. The cat data demonstrated that an IVT injection of DXP emulsion increased IOP to a lesser extent than an equivalent injection of triamcinolone acetonide (TA), with a more rapid return to basal levels. Moreover, at the end of the experimental period, while all the cats treated with TA developed cataract, none of those treated with DXP emulsion developed cataract.
The data collected during these preclinical experiments demonstrated that DXP emulsions are very well tolerated, with a NOAEL at 1280 µg DXP. Thus, confirming the potential of DXP emulsions as a safe alternative for the effective delivery of DXM into the eye.
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