The New Class of Ophthalmic Agents
Here's how to choose the right prostaglandin for the each patient.
BY J. JAMES THIMONS, O.D., F.A.A.O.

Prostaglandins are the first new class of ophthalmic agents to become available for glaucoma therapy since the introduction of beta blockers in 1978. Their use has steadily increased, initially as second-line therapy, but now often as primary therapy to manage many glaucoma diagnoses. Here, I'll provide an overview of the effects of the different prostaglandin drugs.

What they are

At first only a single prost- aglandin agent, latanoprost (Xalatan), was available, simplifying the decision for us. Since then, three new drugs in this category have been released -- travoprost (Travatan), unoprostone (Rescula) and bimatoprost (Lumigan). Each has unique properties that make it best for use in particular circumstances.

The challenge we face is to understand which agent is best for which patient. We must consider the indications, contraindications and side effects of the drugs, plus their overall role in managing glaucoma.

While many practitioners consider prostaglandins to be much like beta blockers, their chemistry is different. Because of this, we can separate prostaglandins according to intraocular pressure (IOP) control, side effects and complications, as follows:

• Latanoprost is an FP receptor agonist, working at the site where IOP is controlled.
• Travoprost has similar chemistry, but significantly higher affinity for the receptor site, and therefore produces greater IOP control relative to latanoprost.
• Unoprostone is a docos- anoid and stimulates a different receptor site than the FP agonist, which means that it has a significantly lesser effect on IOP, but creates a favorable differential for side effects relative to the other drugs.
• Bimatoprost is a prostamide, or ocular hypotensive lipid. Unlike latanoprost and travoprost, it's not a pure FP agonist; it works on other receptor sites.

We can best understand the significance of these differences in chemistry by reviewing the patients' clinical responses to the drugs and the fundamental differences in drug performance.

Lowering IOP

Latanoprost, travoprost, bimatoprost and unoprostone have all been approved for second-line IOP-lowering therapy in FDA trials but have often been used as initial drug therapy for open angle glaucoma. How do you determine which drug is best for your patient? One of the simplest ways is to review the basic performance factors regarding IOP control, incidence of side effects, cost and patient acceptance.

Here's a head-to-head comparison of package insert data regarding IOP:

• Latanoprost demonstrated a mean IOP change of 6.7 mm Hg
• Unoprostone showed a 3 mm Hg to 4 mm Hg change
• Travoprost showed a 7.1 mm Hg change
• Bimatoprost showed a 8.1 mm Hg of change.

The populations of these study groups were generally similar, and subsequent publications have supported this differential in IOP control among the agents.

Another way to look at these data is to analyze the percentage of IOP reduction produced by each drug:

• Latanoprost's mean percentage reduction was 27%.
• Unoprostone's was 15%.
• Bimatoprost's was 33%.
• Travoprost's was 28%.

One of the interesting characteristics of the prostaglandins is their significant IOP-lowering effect in monotherapy. This effect enables us to study the percentage of patients who have pressure reductions below 17 mm Hg. In a publication from the Advanced Glaucoma Intervention Study (AGIS), Douglas Gasterland, M.D., found that the ability to maintain lower IOP significantly affects the progression of optic neuropathy and visual field loss in glaucoma.

Latanoprost, travoprost and bimatoprost all have greater capacity to lower IOP below 17 mm Hg on average than timolol maleate (Timoptic). Latano- prost's capacity is 49.5% of patients, travoprost's is 56.3% and bimatoprost's is 64%. Both travoprost and bimatoprost demonstrate statistically significant differences in ability to lower IOP to below 17 mm Hg on average.

Side effects

While IOP characteristics are critical in evaluating any glaucoma agent, you must also consider the incidence of side effects that each of the agents produces. The two most visible side effects of the drugs are conjunctival hyperemia and iris pigmentation.

Conjunctival hyperemia. This side effect is incidental to the IOP management considerations that lie at the core of your decision making, but it may affect patient acceptance.

With latanoprost, there's an extremely low rate of hyperemic response, but both travoprost and bimatoprost show a greater percentage of patients with ocular hyperemia following initial therapeutic intervention. Bimatoprost shows the most, at approximately 3.5%, with travoprost second at 1.5% and latanoprost third at <1%.

While this side effect can worry patients, remember two things: 1) though it's not uncommon for the eye to become hyperemic upon initial drug instillation, the effect diminishes later; and 2) though latanoprost had a significantly lower level of hyperemia per patient in clinical trials, the average level of hyperemia was no greater than trace in either the travoprost or bimatoprost groups. Educate the patient about possible side effects and help him understand that hyperemia is directly related to the lowering of IOP and as such is worth tolerating temporarily.

Iris pigmentation. Iris pigmentation is a significant concern. There's no evidence that it's reversible, and it plays an important role in patient acceptance of therapy.

As mentioned previously, unoprostone, while less potent at the receptor site for lowering IOP than the other agents, has the lowest rate of iris pigmentation. In a clinical trial, only one patient in the entire cohort demonstrated iris pigmentation change, which places the incidence rate at somewhere in the 0.01% range.

Latanoprost, however, has a published iris pigmentation rate of 6.7% at 6 months -- nearly 16%, or 1 in every 6 patients at 12 months. Travoprost's rate is approximately 3% at 12 months and bimatoprost's is 1.9% in the same time frame. Clearly, bimatoprost and travoprost are markedly superior when it comes to avoiding significant side effects while lowering IOP.

Other side effects such as intraocular inflammation, cystoid macular edema and the reactivation of herpes simplex have very low rates of occurrence. These rates are thought to be relatively equal between the three drugs that produce the greatest IOP reduction. Unoprostone does appear to have a significantly lower occurrence of these side effects, but this has to be compared with its less effective IOP control.

What do they cost?

Another consideration is the cost of these drugs for your patients. The best way to look at the effectiveness of any drug is to understand the cost of the application per mm Hg reduction in IOP achieved. While it appears that beta blockers are more cost-effective, some studies indicate that the cost per unit of IOP reduction isn't significantly lower than prostaglandins -- there's less than a 5% difference.

You must also understand that all bottles don't contain an equal number of drops. The package insert indicates that latanoprost contains approximately 90 to 95 drops, travoprost contains 100 to 105 drops and bimatoprost contains 105 to 111.

In a separate study using real patients and measuring the effective availability of drops (multiple drops dispensed simultaneously, spillage rate, etc.), latanoprost showed a significant reduction in available drops per bottle, to approximately 75 to 80. Travoprost stayed in the 100 to 105 range and bimatoprost dropped into the mid 90s. Clearly, there's a consistent difference in the number of drops per bottle in a system in which the price point for purchase for the drugs is approximately the same in most markets.

Another consideration regarding the cost to the patient is that bimatoprost is the only prostaglandin that comes in a 5-ml bottle. For patients who have prescription plans that require co-payments, this reduces the number of co-payments by half over a year.

Preservatives and stability

You should also consider two other relatively minor but possibly influential points:

• the levels of preservative in the drug and the potential toxicity or medicamentosa they can induce if used chronically
• the stability these drugs demonstrate at room temperature.

Preservative levels vary considerably, with latanoprost showing a 0.02% benzalkonium chloride (BAK) base while unoprostone and travoprost use 0.15% BAK base. Bimatoprost demonstrates a 0.005% BAK concentration. It's certainly possible that preservatives could affect the eye's ability to tolerate a medication that's used chronically.

It's been known for some time that latanoprost is susceptible to heat. Exposure to temperatures higher than 47 degrees F. decreases the drug's concentration by almost 18% over time. Neither travoprost nor bimatoprost requires refrigeration, and both have relatively broad ranges of temperature stability, with latanoprost's being slightly greater than bimatoprost's.

While neither of these points may seem critical, effectiveness may be impacted by how a patient stores the drug. The lack of a refrigeration requirement for these drugs is a factor in ease of use and long-term efficacy.

Other considerations

Other considerations you should review in your selection of the appropriate prostaglandin agent include the following:

The differential of IOP control by race. This was first established with the release of travoprost, which in clinical studies showed a clear difference in IOP control compared with latanoprost for African-American patients. The average IOP difference between the two drugs is approximately 1.5 mm Hg, a consistent finding throughout the study periods. Bimatoprost has also been shown to have a differential effect by race.

The percentage of patients who are non-responsive to initial therapeutic intervention, and the separation of effect from one drug to another based on chemical class. While all prostaglandins are superior to timolol maleate, 1 in 11 patients (8.9%) is non-responsive to latanoprost. Travoprost and bimatoprost have significantly lower non-response rates of approximately 3% to 4%.

Consider switching agents if the therapeutic effect is minimal, for there is some clinical evidence that different patients will respond differently to these drugs.

A new dimension

The prostaglandins have added a new dimension to glaucoma care and can impact your success. The key is to understand that significant differences exist between these agents and that you can use them to improve the quality of care you provide.

J. James Thimons, O.D., F.A.A.O., is from Ophthalmic Consultants, a multi-specialty surgical practice, and TLC Laser Center in Fairfield, Conn. He's also Optometric Management's clinical director.