Alcaftadine 0.25% a new option

The latest addition to the antihistamine arsenal is alcaftadine ophthalmic solution 0.25% (Lastacaft, Allergan), a new chemical entity developed as an ocular anti-allergic agent.

Although it is structurally related to ketotifen, alcaftadine has a number of properties that distinguish it from comparable topical medications. For instance, the agent is a high-affinity antagonist at both the H₁ and the H₂ histamine receptors and also has demonstrated antagonism at H₄ histamine receptors. This pharmacologic spectrum is unique and may help explain alcaftadine's long duration of action.

In addition, alcaftadine has demonstrated significant epithelial stabilization characteristics. In pre-clinical studies, the agent showed a protective effect on two major protein components of conjunctival tight junctions: zonula occludens-1 and E-cadherin. These proteins normally function as integral components of the conjunctival epithelial barrier, and a number of recent studies have suggested that breakdown of this barrier may underlie aspects of allergic conjunctivitis.

The primary endpoints were ocular itching and conjunctival redness, and by using two separate CAC challenges it was possible to measure both the onset and the duration of drug action. Secondary endpoints included ciliary and episcleral redness, chemosis, lid swelling, tearing, ocular mucous discharge, and nasal symptoms (sneezing, rhinorrhea, nasal congestion, nasal pruritus, and ear or palate pruritus). Nasal symptom composite scores also were calculated.

Onset, duration of action

Subjects (170 in total) were randomly assigned to one of five treatment groups: alcaftadine 0.05%, 0.1%, or 0.25%, placebo control, or active control (olopatadine 0.1%). To evaluate onset of action, responses were measured starting at 15 minutes after study medication instillation.

The average score of both eyes was used as the response variable for all analyses. All active treatment groups (n = 34) were clinically (≥1 unit difference) and statistically (p < 0.001) superior to placebo at all time points for prevention of ocular itching.

All groups also were statistically different from placebo in preventing redness at the first post-CAC evaluation, as were the alcaftadine 0.25% and olopatadine treatment groups at later time points. Mean redness scores for olopatadine and alcaftadine 0.25% achieved clinical significance (≥1 unit difference) compared with placebo at the first post-challenge time point. Thus, alcaftadine 0.25% provided an overall onset of action that was comparable with the active control.

At the 16-hour post-CAC evaluation, all three alcaftadine concentrations produced lower mean ocular itching scores than both placebo and olopatadine. All active treatment groups reached clinical and statistical significance relative to placebo at all time points, with the exception of clinical significance for olopatadine the first post-challenge time point.

The mean conjunctival redness scores also were lower for alcaftadine treatment groups and the olopatadine treatment group compared with placebo, and the alcaftadine 0.25% and olopatadine groups reached statistical significance for mean redness scores (versus placebo) at all post-challenge time points. Only alcaftadine 0.25% produced mean scores that showed a clinically significant difference from the placebo group at the first two time points post-CAC.

Dosing rationale

Overall, the study established that, at the 0.25% dose, the duration of alcaftadine action was at least 16 hours, thus providing a rationale for the dosing used in the approved product and for the once-daily indication.

Both alcaftadine 0.25% and olopatadine treatment groups exhibited a statistically significant reduction in mean scores (versus placebo) for all secondary endpoints including ciliary and episcleral redness, chemosis, lid swelling, tearing, ocular mucous discharge, and nasal symptoms.

The incidence of adverse events in the study was low, and the events were self-limiting, resolved without treatment, and were graded as mild or moderate by the investigators. The most common non-ocular adverse event was nasopharyngitis, reported in a total of six subjects (3.5%): one each in the placebo and alcaftadine 0.25% groups, and two each in the alcaftadine 0.05% and olopatadine groups.

The key finding from this study was that alcaftadine 0.25% exhibits a strong persistency of allergic relief.

The efficacy of alcaftadine 0.25% in preventing the signs and symptoms of allergic conjunctivitis 16 hours after a single dose may suggest a lasting protective mechanism. The spectrum of properties displayed by alcaftadine demonstrates that it is an antihistamine with a combination of high efficacy and once-daily dosing convenience.

Jack V. Greiner, DO, PhD, is on the faculty at the Schepens Eye Research Institute, Boston, and the Department of Ophthalmology, Harvard Medical School, Boston. He has no financial interest in the subject matter.