Topical drugs reach the back of the eye

Direct ocular administration is probably preferable to the systemic route, says physician.

DALLAS – Topically applied drugs may reach retinal tissue in sufficient quantity to be efficacious in neuroprotective treatment, according to a study presented here. Alexander R. Kent, MD, and colleagues found that topically administered brimonidine reached sufficient concentration levels in the vitreous to suggest possible neuroprotective efficacy.

Speaking to colleagues here at the annual meeting of the American Academy of Ophthalmology, Dr. Kent said he believes that a glaucoma drug is needed that will act directly on retinal ganglion tissue to prevent neuronal apoptosis, field loss and subsequent blindness. Just what pathway that drug will take to its target tissue has yet to be determined.

Noting that the lowering of intraocular pressure (IOP) “is itself neuroprotective,” Dr. Kent said future medical therapies for glaucoma would directly target retinal ganglion cells as well as the regulation of IOP. “The challenge is to get these drugs to reach the target tissues,” he said. “In this case, it’s the retinal ganglion cells, the optic nerve head and its supportive structures, and the vasculature.”

Reaching the retina

Dr. Kent and colleagues performed a study to determine the penetration of brimonidine into the vitreous over 4 to 14 days prior to vitrectomy. Dry vitrectomies were performed and analyzed independently.

Evaluating the concentrations of brominidine found in the vitreous, the researchers found that these concentrations were well above the 2 nm threshold, even in phakic patients. “The phakic patients had a lower nm concentration than the pseudophakes,” he said, “and the aphakes had a little bit less, but in general it was very high.”

Dr. Kent noted that 2 nm is the laboratory determination of the activation of the alpha-2 receptor, which is supposed to be required for neuroprotection.

Formidable barriers

Topical delivery is the most common pathway for delivery of current glaucoma drugs, but Dr. Kent noted that it is a complicated route from the anterior eye structures to the target cells of the retina.

“There are many barriers to entry for a topical drop to get back to the posterior pole,” he said. These include precorneal washout via the nasolacrimal system, penetration through both lipophilic and hydrophilic corneal layers, absorption by anterior segment stuctures, dilution, protein binding in the posterior chamber causing non-bioavailability and other factors, he said.

The natural lens is a formidable barrier, acting as a “ball valve,” he said, the iris and lens creating a seal that prevents the drug from moving posteriorly through the aqueous.

Once the drug is in the vitreous, “it’s going to be diluted again, 5 mL to 6 mL,” Dr. Kent said. “There is going to be an effect of any protein binding on the protein in the vitreous which will make it not bioavailable. And there may be some clearance by the vasculature in the choroid and ciliary body.” And the drug has to be biologically available: that is, unbound to protein. “The drug needs to bind to receptors in a sufficient concentration to have a sustained effect and still be subtoxic to the retina,” he continued.

Systemic delivery concerns

Another option may be to administer neuroprotective drugs systemically, Dr. Kent said. “In this way it would enter through the vasculature into the target cells and cause some sort of desired effect.”

The systemic pathway, however, presents challenges. The main problem is crossing the blood-retina barrier. Other potential limitations to the systemic route include possible undesirable side-effects to the nervous system or negative hemodynamic changes. “There may be some agents which change optic nerve blood flow, and the problem there with systemic administration is dilation of systemic vascular beds may cause a steal syndrome,” Dr. Kent said. Nervous system side effects include mood changes or fatigue syndromes, he noted.

Other alternatives

Few alternatives to topical ocular or systemic administration are available at this time, Dr. Kent said, though he indicated sub-scleral or sub-conjunctival pathways may be considered.

“Sustained delivery devices, including Ocusert, have been very successful, but on a limited scale,” he said. “Subconjunctival delivery devices will also be coming down the pike.”

Advantages of these routes include increased tear contact time, lower quantity of drug with consistent delivery, and decreased systemic effects.

Osmotic pumps placed in the eye are another possibility. The Vitrasert, an implant that delivers ganciclovir to the posterior segment in cytomegalovirus retinitis patients, is an example of this mode of delivery.

“So I think we need to prove that a drug delivery device is neuroprotective and there needs to be prospective, longitudinal studies comparing them to controls. I think we can get back to the posterior pole and this will depend on the route of administration.”

For Your Information:

• Alexander R. Kent, MD, is an assistant professor at the Medical University of South Carolina. He can be reached at the Storm Eye Institute, 171 Ashley Ave, Charleston SC 29425; (843) 792-3134; fax: (843) 792-1166; e-mail: kentar@mucs.edu. Dr. Kent has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.