The concept of receptor occupancy to predict clinical efficacy: a comparison of second generation H1 antihistamines.

Second generation H1 antihistamines are considered first-line therapy for allergic rhinitis and chronic idiopathic urticaria, largely because of their nonsedating effects. Evaluating pharmacokinetic and pharmacodynamic parameters and clinical efficacy of a drug is important, but models to predict clinical efficacy are lacking. Receptor occupancy (RO), a predictor for human pharmacodynamics and antihistamine potency that takes into account the affinity of the drug for the receptor and its free plasma concentration, may be a more accurate way to predict a drug's clinical efficacy. This study was designed to assess the concept of RO as a surrogate for clinical efficacy, using examples of second generation oral antihistamines. A literature review was conducted using MEDLINE. Search terms included allergy, allergic rhinitis, drug efficacy, over-the-counter drugs, perennial allergic rhinitis, seasonal allergic rhinitis, second generation antihistamines, chronic idiopathic urticaria, and treatment outcomes. Abstracts and posters from recent allergy-related society meetings were also used. RO of several second generation H1 antihistamines was derived from noncomparative and head-to-head studies. Fexofenadine and levocetirizine showed similar RO at 4 hours, both higher than that of desloratadine. Levocetirizine established higher RO than fexofenadine or desloratadine at 12 and 24 hours. RO for these agents appeared to correlate with pharmacodynamic activity in skin wheal and flare studies and with efficacy in allergen challenge chamber studies. Parameters affecting RO included time from dosing, pH, and dosing regimen. RO did not appear to be linearly related to drug concentration. Results indicate that RO is an accurate predictor of in vivo pharmacodynamic activity and clinical efficacy.