Research Digest

■ Comparison of In Vitro Receptor Binding of Glucocorticoids Reveals Pharmacokinetics Key to Efficacy

The differences in receptor-binding potency among the three currently studied intraocular glucocorticoids, using a human recombinant receptor binding assay, indicate that triamcinolone acetonide (TA) and fluocinolone acetonide (FA) are essentially similar, and somewhat more potent than dexamethasone. These results were presented at the 2007 Association for Research in Vision and Ophthalmology in Fort Lauderdale, Fla.

Tritiated dexamethasone was competitively bound to a cell membrane preparation of a human recombinant glucocorticoid receptor with varying concentrations of dexamethasone, TA and FA over 16 hours. The investigators found TA and FA had modestly greater binding affinity (Dexamethasone Ki ~ 10x FA/TA Ki.) Dexamethasone is the corticosteroid used in the Posurdex (Allergan, Irving, Calif.) insert and FA is in Medidur (Alimera Sciences, Atlanta). TA treats certain retinal conditions via a bolus injection in the vitreous cavity.

Ken Green, Ph.D., chief scientific officer of Alimera Sciences and one of the co-investigators on the study, spoke with Ophthalmology Management about these results. "This data is useful now as these different therapies are contemplated," Dr. Green said. "It's interesting that the approximate relative daily doses, delivered by Posurdex (approximately 12 μg) and Medidur (0.5 μg), reflect the trend observed in this study, although I wouldn't necessarily assume a significant difference in clinical effect."

"Of course, properties such as solubility will be important, in addition to the technology used to deliver these steroids." Dr. Green notes. "Because FA is delivered via Alimera's Medidur technology, patients in this study receive the lowest daily dose of a corticosteroid among those being studied. This has the greatest potential to contain the drug to the posterior segment and minimize side effects, especially IOP."

Asked whether the issue of the sustained release of dexamethasone and FA vs. the immediate release of TA had significance for the treatment of ophthalmic disorders, Dr. Green noted, "TA clearly forms an insoluble depot in the back of the eye that appears to release drug over approximately 30 days, whereas dexamethasone is delivered via a bioerodible insert, which is reported to erode over approximately 45 days. FA, delivered via the Medidur technology, releases drug over a period of years."

The phase 3 Medidur trial is studying different doses. "No one really knows how low the dose can go and still achieve a therapeutic effect. The goal is to administer the lowest effective dose, because this increases the chance of containing the drug to the back of the eye." OM

■ Glaucoma Device Reduces Postoperative Hypotony

A study published in the January 2007 issue of the Journal of Glaucoma compared the efficacy and safety of trabeculectomy vs. the Ex-Press (Optonol Ltd., Neve Ilan, Israel) miniature implant in the treatment of glaucoma, finding the implant had a statistically significantly lower incidence of postoperative hypotony and choroidal effusion.

Speaking with Ophthalmology Management, Peter A. Netland, M.D., Ph.D., of the Hamilton Eye Institute, University of Tennessee Health Sciences Center, and corresponding author for the study, said the lower hypotony rate in Ex-Press patients "was a significant benefit clinically because it improves the safety of the procedure and makes it more predictable."

Trabulectomy, Dr. Netland said, is the "gold standard of primary glaucoma surgery." However, there are inherent risk. "Sclerectomy not only causes inflammation and some tissue loss," Dr. Netland said, "but it also introduces quite a bit of variability in the results because the opening that the surgeon makes is fairly variable."

The Ex-Press implant may be an improvement on trabulectomy because of the smaller opening in the sclera, Dr. Netland continued, referring to the 50-μm internal diameter of the Ex-Press implant. "If you have a really small opening, that in and of itself will provide some resistance to aqueous flow, where the pressure has a harder time dropping to 0," Dr. Netland said.

"I think they're directly related," Dr. Netland said about the lower incidence of choroidal effusion along with hypotony in the Ex-Press cohort. "The patients are set up to develop choroidal effusions because their IOPs are so low that the effusions are a consequence."

In most other ways, the Ex-Press implant had very similar efficacy to classic trabeculectomy. Asked whether greater differences might be seen in the future, Dr. Netland said, "I think that may be something that can be changed by some newer Ex-PRESS implant designs that have bigger openings." OM