Agent's activity profile targets ocular allergy symptoms

Kansas City, MO-Olopatadine HCl (Patanol, Alcon Laboratories) offers a unique pharmacologic profile of activity that corresponds to its unsurpassed efficacy in the management of allergic conjunctivitis, according to the results from comparative studies published in the peer-reviewed literature, said Lanny J. Rosenwasser, MD.

Dr. Rosenwasser was the lead author of a recent article [Curr Med Res Opinion 2005;21:1377-1387] that reviewed publications on in vitro, animal, and clinical studies evaluating olopatadine. Those papers showed that olopatadine can be differentiated from other agents used in the management of ocular allergy by its dual mechanism of action. It combines highly potent and selective antihistaminic activity with mast cell stabilizing properties across a range of concentrations, including the 0.1% concentration found in the marketed product of olopatadine.

"Preclinical studies reveal that olopatadine has some unique effects on conjunctival mast cells with a superior ability to stabilize the cell membrane and inhibit the release of histamine and other allergy mediators," said Dr. Rosenwasser, Dee Lyons/ Missouri Endowed Chair in Pediatric Immunology Research and professor of pediatrics, allergy-immunology division, Children's Mercy Hospital, Kansas City, MO. "Considering that conjunctival mast cells are a primary therapeutic target for topical allergy medications, it is not surprising that the benefits of olopatadine in those in vitro tests are matched by its superior performance in clinical trials. These benefits can be defined by greater relief of itching and a singular ability to control the broader spectrum of clinical signs and symptoms associated with ocular allergy."

Key findings

Results from a number of in vitro and preclinical studies demonstrated that olopatadine exhibits high affinity for the H₁ receptor and potently inhibits its binding of histamine.

In addition, olopatadine has selectivity for the H₁ receptor exceeding that of several other antihistamines used in the management of ocular allergy.

In an early in vitro study evaluating the effects of olopatadine and ketotifen fumarate ophthalmic solution (Zaditor, Novartis) on human conjunctival mast cells, olopatadine exhibited a dose-related inhibition of histamine release, whereas ketotifen suppressed histamine release at low concentrations, but had a stimulatory effect at a higher dose.

"This difference in activity between the two compounds provided an initial indication that olopatadine has a potentially broader margin of efficacy and safety than ketotifen," said Dr. Rosenwasser, who is also professor of medicine, pediatrics, and basic science, University of Missouri-Kansas City School of Medicine.

Furthermore, while other anti-allergy compounds had demonstrated efficacy in inhibiting histamine release from mast cells in rodent models, only olopatadine demonstrated dose-dependent activity and antihistamine effects at clinically relevant concentrations when the drug effects were tested in a study using cultured human conjunctival mast cells.

"Mast cell populations are heterogeneous and so it is important to evaluate the activity of anti-allergy drugs using appropriate models," Dr. Rosenwasser said.

In another study evaluating the mast cell membrane effects of a number of marketed preparations of ocular allergy medications, including olopatadine, ketotifen, azelastine HCl (Optivar, MedPointe Pharmaceuticals), and epinastine (Elestat, Allergan), olopatadine was the only compound that did not promote membrane perturbation, and it alone inhibited human mast cell histamine release.

"By inducing mast cell degranulation, these other anti-allergy agents may cause ocular surface irritability that can compromise patient acceptance and compliance," Dr. Rosenwasser said.

Results of placebo-controlled clinical studies using the gold standard conjunctival allergen challenge model showed olopatadine offered rapid onset of anti-allergy action and a prolonged duration of activity of at least 8 hours, which minimizes dosing frequency and encourages compliance. In those studies, its clinical benefits were measured by significant inhibition of the development of ocular itching and hyperemia, and its efficacy has also been demonstrated in placebo-controlled environmental studies.

In addition, olopatadine demonstrated superiority for reducing itching when compared with both ketotifen and azelastine in prospective, randomized, double-masked trials using the conjunctival antigen challenge model.

"Both ketotifen and azelastine are considered to be dual action antihistamine/mast cell stabilizers, but they are only indicated for controlling itching whereas olopatadine has demonstrated significant benefits in clinical studies for relieving a broader spectrum of signs and symptoms of allergic conjunctivitis," Dr. Rosenwasser said.