Glaucoma Drug Debate Continues at AGS Meeting
Are all of the prostaglandin analogues the same?
BY DESIREE IFFT, EXECUTIVE EDITOR

Attendees of the American Glaucoma Society meeting in March crowded into the oral presentation room to hear about the newest research into prostaglandins and prostamides. Especially spirited question-and-answer sessions followed two of the presentations pertaining to the mechanism of action of these drugs. Both of those studies sought to contribute to the understanding of whether bimatoprost is a prodrug that lowers IOP by the same mechanisms as the other drugs marketed in the class (latanoprost and travoprost) or whether it is a unique drug that binds with a unique receptor.

Some scientists maintain that the efficacy of bimatoprost (Lumigan), latanoprost (Xalatan) and travoprost (Travatan) is attributable to the same, single process: They are cleaved by the cornea and hydrolyzed, or converted, to their free acids, which then bind with and activate the F-prostanoid (FP) receptor to reduce IOP. Others maintain that hydrolysis does not account for the efficacy of bimatoprost and that the amide, which is not hydrolyzed, is also acting to reduce IOP -- at a unique "prostamide" receptor.

One way to investigate the issue is to measure the amounts of bimatoprost free acid in the aqueous humor after topical instillation of the drug. Carl Camras, M.D., et al. and Louis Cantor, M.D., et al. performed such studies, for the first time in human eyes, and presented their findings at the meeting.

Two Studies, Two Conclusions

In the Camras study, patients scheduled for cataract surgery were dosed with bimatoprost 0.03% or vehicle once a day for 7 days prior to surgery. The last drop was administered 2 or 12 hours before collection of aqueous humor prior to surgery. The specimens were assayed for bimatoprost and its free acid by high-pressure liquid chromatography and mass spectrometry. The findings:

► At 2 hours following the last dose, aqueous humor concentrations of the free acid were 22.0 ± 7.0 nM (n=12).

► At 12 hours following the last dose, concentrations of the free acid were 7.0 ± 4.6 nM (n=8).

From the data, Dr. Camras concluded that because levels of a known prostanoid receptor agonist (bimatoprost free acid), sufficient to lower IOP, are achieved in the aqueous humor after bimatoprost instillation, there is no reason to theorize about the existence of a novel receptor. "The Cantor study detected low levels of the free acid, but still plenty to activate the prostanoid receptors," he said.

In the Cantor study, 40 patients scheduled for cataract surgery were dosed with a single 30-microliter drop of bimatoprost 0.03% or placebo at 1, 3, 6 or 12 hours before the surgery. Aqueous humor samples were analyzed for bimatoprost and 17-phenyl trinor PGF2a (the bimatoprost free acid) using HPLC-tandem mass spectrometry. The findings:

► At 1 hour after the single dose, the free acid levels averaged 5.1 nM.

► At 3 hours after the single dose, the free acid levels averaged 6.7 nM.

► At 6 hours after the single dose, the free acid levels averaged 1.9 nM.

► No acid metabolite was quantifiable in any of the 12-hour samples.

Dr. Cantor concluded that levels of the acid hydrolysis product of bimatoprost were low or absent in the aqueous humor. The average concentrations detected, he said, were substantially lower than the concentrations of latanoprost acid reported by Sjquist and Stjernschantz in Survey of Ophthalmology in 2002. Levels in that study peaked at approximately 100 nM. Therefore, Dr. Cantor said, his current results further support the idea that hydrolysis does not account for the IOP-lowering power of bimatoprost.

Ophthalmology Management spoke with Drs. Camras and Cantor and other experts after the meeting.

Both studies used the commercial formulation of bimatoprost, but as indicated above, at different dosing schedules. "With prolonged dosing, you would expect to get higher levels of drug in the eye," Dr. Cantor said. "But the fact is all of these drugs have an effect after one drop, and the levels detected in these two studies are not whole orders of magnitude different. They're fairly similar."

Hotly Debated Issue

Robert D. Fechtner, M.D., F.A.C.S., sat in on both presentations. Of the question-and-answer sessions, he said: "That was spirited scientific challenge over what has remained a hotly debated issue for several years now. We've not yet received a definitive answer on this. Both studies found free acid at rather similar levels in the aqueous. The presence of free acid does not necessarily explain the mechanism, but if it is present at sufficient levels it would at least offer the possibility that bimatoprost is working at the same receptors as latanoprost and travoprost. Both investigators found low levels of free acid, but was it sufficient? The investigators and others in the audience clearly did not agree on this point."

Clinicians need to critically assess the information that's being provided to them and ask if it's supported by the literature, Dr. Fechtner said. "You could ask whether these studies are 'just test-tube science' or if they're going to help the clinician someday. A clearer understanding of the mechanisms of these drugs may ultimately allow for the development of the next generation of medications with an optimal combination of efficacy and tolerability."

For most clinicians, Dr. Cantor said, as long as a drug is safe and effective, how it works is not that important. "To this day, we really don't completely understand how topical beta blockers work to lower pressure," he said. "However, it is very important if we want to understand glaucoma, how the eye's outflow mechanisms work, and how they can be manipulated pharmacologically.

"What has been proposed -- that bimatoprost works differently than latanoprost and travoprost -- is new. And when you have something new, questioning and skepticism are typical, even healthy. If there is indeed a novel type of recepor that a drug might bind with, it opens up a whole new class of potential drugs that we can use to go after that receptor. Before the prostaglandin receptor was known, we would have never thought to use drugs to manipulate it."

Other Avenues of Investigation

Whether there's free acid, and how much is important in the aqueous, isn't all that needs to be studied, Dr. Cantor said. Several lines of research are building around the mechanism of action question. He explained three of them:

What are the different possible routes of drug penetration into the eye? "There's evidence in primate data from Woodward and Kraus and others that suggests that the primary site of penetration of bimatoprost is not via the cornea, and therefore into the aqueous, but via the sclera directly into the ciliary body and the uvea. So the aqueous levels only give us one small part of the equation. We need to also understand what's going through this other scleral route and what the level of free acid may be in the ciliary body itself, since this is the actual site of action of the drug. In the primate studies, nearly 100-fold more drug was getting into the ciliary body than what would penetrate through the cornea."

How much free acid is needed for a functional effect? "We need to determine the functionality and potency of these free acids. The bulk of the literature suggests to me that the free acids of the prostaglandin and prostamide drugs have similar potency at the receptor. If that's true, then the levels of bimatoprost are not high enough to have an effect. The only way to postulate that bimatoprost works by its free acid is to demonstrate that the free acid is much more potent and you therefore don't need as much of it. But I don't think there's compelling and consistent evidence of that to date. Of course, there's some disagreement on that."

Can we find a new receptor? "There is some early evidence that bimatoprost works by binding to a novel receptor, but the receptor certainly has not been characterized and identified and described yet, so it's an unknown. That doesn't mean it doesn't exist. It just means there's a lot of work to do. It took 20 years to find the prostaglandin receptor. We're early in the game with the prostamide."

Another study, by David Woodward, Ph.D., and others, presented during the same AGS session, examined the effect of bimatoprost on the expression of two remodeling genes, Cyr61 and CTGF, and its effect on the morphology of ciliary muscle and trabecular meshwork. In that study on primates, the bimatoprost amide upregulated expression of Cry61 in ciliary muscle cells only. In contrast, PGF2a (free acid) increased the expression of both Cry61 and CTGF in ciliary muscle and trabecular meshwork cells. This indicates, Dr. Woodward said, that two different populations of receptors are involved in ciliary muscle, one sensitive to the amide, another sensitive to PGF2a.

"This study also greatly expanded our knowledge of how bimatoprost affects uveoscleral outflow," he said. "This is the first time we've been able to see the morphological results of long-term treatment with a commonly prescribed anti-glaucoma drug. We now have results of 1 year of daily treatment.

"We found the creation of new drainage channels in the ciliary body. They appear very organized, are partially lined with endothelial-like cells, and are almost invariably associated with blood vessels. They resemble lymphatics. Clearly, a well-organized remodeling occurs. The remodeling is very localized and appears to be the only morphological event resulting from long-term treatment with bimatoprost."

No Questions on Efficacy

Regardless of the scientific questions surrounding the prostamides and prostaglandins, Dr. Fechtner said, "we now have a very efficacious class of drugs that will continue to play a crucial role in the care of glaucoma patients well into the future."

Dr. Camras is a consultant to Pfizer Ophthalmics.

Dr. Cantor has received research funds from Allergan, Pfizer, Alcon, Merck and Santen, and is on the Allergan Glaucoma Advisory Board and Speaker's Bureau.

Dr. Fechtner is a consultant to and has received research support from Pfizer. He has also received research support from Allergan.

Dr. Woodward is an Allergan employee.