Desloratadine: A preclinical and clinical overview

A new competitive histamine H(1)-receptor antagonist with superior binding affinity at this receptor as compared with other common antihistamines, desloratadine is the active metabolite of loratadine, the most extensively used agent of this class. Under development for the treatment of allergic rhinitis and urticaria and currently awaiting regulatory approval in the United States, desloratadine was recently approved and became commercially available in Europe for the treatment of allergic disease. Desloratadine is at least 50-fold more potent in vitro and appears to be 10-fold more potent in vivo than loratadine. The new antihistamine is metabolized to 3-hydroxydesloratadine, which retains biological activity. Absorption of orally administered desloratadine is dose proportional, and desloratadine achieves steady-state concentrations after approximately 5 doses with once-daily administration. This is consistent with mean half-life values of 24-27 h and a 24-h dosing interval. The absorption of desloratadine is not affected by food and there are no clinically relevant drug-drug interactions. In randomized, double-blind, placebo-controlled clinical trials, a single 5 mg dose of desloratadine conferred significant relief of seasonal allergic rhinitis (SAR) symptoms - including the complaint of nasal congestion - within hours of the first dose, and these effects were sustained both for the entire 24-h dosing interval and up to 2-4 weeks with once-daily treatment (5 mg/day). In addition, patients with seasonal exacerbations of mild to moderate asthma derived similar clinical benefits from desloratadine, with significant, first-dose relief of both SAR-related complaints such as nasal congestion as well as asthma symptoms. In addition, beta(2) agonist requirements for symptom management were significantly reduced from baseline in these asthma patients when treated with the 5 mg/day desloratadine regimen as compared with placebo. Also experiencing marked relief of symptoms upon treatment with desloratadine were patients with chronic idiopathic urticaria, who exhibited significant first-dose relief of pruritus and sustained reductions in this symptom, numbers of lesions (and size of largest hive) and sleep disturbances, with a marked improvement in their ability to carry out activities of daily living. The clinical benefits of desloratadine in the above clinical settings were accompanied by general improvements in quality of life. Desloratadine does not cross the blood-brain barrier, as demonstrated by both human studies using cognitive indices as well as work in animal models. Desloratadine is well tolerated, and no significant drug-related (or food-related) adverse effects were noted when the agent was administered together with cytochrome P450 inhibitors (e.g., ketoconazole, erythromycin). Administration of desloratadine has not been shown to cause any significant changes in cardiac activity at therapeutic doses, even at 9-fold higher doses, or in the presence of P450 inhibitors. Nor does administration of desloratadine lead to sedation, even in the presence of alcohol. (c) 2001 Prous Science. All rights reserved.