Alcaftadine, a new antihistamine with combined antagonist activity at histamine H₁, H₂, and H₄ receptors

Annabelle C Gallois-Bernos,¹ Robin L Thurmond<sup>2

1</sup>Johnson & Johnson Vision Care Inc, Jacksonville, FL, ²Janssen Research and Development, San Diego, CA, USA

Abstract: Current therapy for ocular allergy includes H₁ antihistamines, mast cell stabilizers, dual action antihistamines (H₁ antihistamines + mast cell stabilizers), and steroids. In this report, we describe the in vivo and in vitro characterization of alcaftadine, a recently approved antihistamine that exhibits a distinct set of therapeutic properties. When tested in a guinea pig model of conjunctivitis, alcaftadine prevented immediate allergic responses with an efficacy comparable with that of ketotifen, and was also able to attenuate delayed eosinophil influx with a potency similar to that of dexamethasone. Given recent reports suggesting a possible role for histamine H₂ or H₄ receptors in the etiology of ocular allergy, we examined the binding properties of alcaftadine at all histamine receptor types. Alcaftadine is a high affinity ligand for the H₁ receptor, with a pK_i (8.5) that is comparable with that of other H₁ antihistamines. It also shows an higher affinity for the H₂ receptor than ketotifen. Alcaftadine exhibited modest binding affinity for the H₄ receptor (pK_i = 5.8) with no affinity for the H₃ receptor. The affinity for the H₄ is higher than the value for ketotifen (pK_i < ₅). Using a cellular assay of H₄ receptor activity, alcaftadine was shown to act as a functional antagonist of H₄ receptor signaling. Overall, the studies suggest that alcaftadine is a histamine receptor antagonist with a broad spectrum of antihistamine activity and a unique combination of therapeutic effects. As such, it represents a new therapeutic option for the treatment of allergic conditions.

Keywords: ocular, allergic conjunctivitis, antihistamine, ketotifen, pheniramine