Predicting and Establishing the Clinical Efficacy of a Histamine H1-Receptor Antagonist

Desloratadine, the Model Paradigm

Glenis Scadding


Clin Drug Invest. 2005;25(3):153-164. 

In This Article

Application of the Model Paradigm

Desloratadine: Affinity and Specificity for H1 Receptors

The efficacy of an antihistamine is mediated, in part, by its specificity, affinity and avidity to the H1 receptor. The in vitro pharmacology of desloratadine on the human H1 receptor was studied using Chinese hamster ovary cells.[13] Desloratadine demonstrated marked H1-receptor binding affinity to these cells compared with other commonly used antihistamines, including cetirizine, ebastine, fexofenadine and loratadine.[13] Similar to other second-generation agents, desloratadine exhibited noncompetitive antagonism of the human H1 receptor, as well as high specificity with a very slow dissociation rate.[13] Competitive-binding studies indicated that desloratadine has approximately a 50-200 times greater affinity for the human H1 receptor than cetirizine and fexofenadine, respectively ( table I ).[13] These results are consistent with earlier data showing desloratadine to be 52-355 times more selective for the human H1 receptor than human muscarinic receptors.[13] However, the clinical significance of these in vitro findings has not been determined in comparative clinical trials.

Antiallergic and Antihistaminic Effects of Desloratadine

In vitro studies with desloratadine revealed that the antihistamine inhibits the expression or release of some inflammatory mediators that may contribute to allergic disease.[22] Desloratadine has been shown to block the action of histamine and other mediators and to inhibit both early- and late-phase reactions.[23] Desloratadine inhibited IgE- and non-IgE-mediated histamine release from human basophil leukocytes at micromolar concentrations in a dose-dependent manner.[24] In contrast, first-generation antihistamines have inhibited histamine release at low concentrations, but stimulated release at higher concentrations.[25]

The ability of desloratadine to inhibit the generation and release of a variety of inflammatory mediators from human tissue and blood cells has been demonstrated in several studies. Using human skin and lung tissues, therapeutic concentrations of desloratadine reduced the number of preformed and de novo synthesised mediators following antigen challenge.[26] Specifically, desloratadine inhibited the release of histamine, prostaglandin D2 (PGD2), leukotriene C4 (LTC4), and tryptase from human-derived basophils and mast cells. In a study investigating an effect on cytokine release, desloratadine significantly reduced the secretion of IL-3, IL-6, IL-8, tumour necrosis factor-alpha (TNF-α), and granulocyte macrophage colony-stimulating factor (GM-CSF) from human leukaemic mast cells compared with cetirizine (figure 2).[6] A study using human basophils showed desloratadine inhibited IgE-mediated histamine and LTC4 release and reduced, to a much greater extent, the secretion of IL-4 and IL-13, with a concentration-dependent effect.[22]

Figure 2.

Comparison of mediator inhibition by the histamine H1-receptor antagonists desloratadine and cetirizine (adapted with permission from Lippert et al. and Blackwell Science[6]). GM-CSF = granulocyte-macrophage colony-stimulating factor; IL = interleukin; TNF = tumour necrosis factor. * p < 0.05 compared with cetirizine.

Desloratadine caused a marked reduction in histamine-induced membrane expression of intercellular adhesion molecule (ICAM)-1 and human leukocyte class II antigens in a study using human epithelial cells.[27] In nanomolar concentrations, desloratadine inhibited endothelial expression of P-selectin - a surface molecule responsible for the adhesion of neutrophils and eosinophils to endothelial cells - and reduced the secretion of IL-6 and IL-8.[28] In a study that used eosinophils from patients with allergic rhinitis or allergic asthma, desloratadine inhibited platelet-activating factor-induced eosinophil chemotaxis and TNF-α-induced eosinophil adhesion in a concentration-dependent manner.[29] Furthermore, desloratadine significantly inhibited phorbol myristate acetate-induced generation of superoxide radicals, which are also implicated in the pathophysiology of allergic disease. A recent discovery that desloratadine inhibits nuclear factor-κB may be the underlying explanation for much of this extra anti-inflammatory activity.[30]

In vitro findings may correlate with the antiallergic effect of an antihistamine, as well as some of its clinical characteristics. The potency, slow dissociation rate, and noncompetitive binding of desloratadine were predictive of its antihistaminic activity and long duration of action. The ability of desloratadine to inhibit the generation and release of histamine and other mediators of inflammation and to block immunological inflammatory processes indicated that it should have a broad, systemic anti-inflammatory effect on both early- and late-phase responses. Together, these results suggested that desloratadine should have a strong and durable antiallergic effect, a concept that was tested in animal models and clinical trials.

In Vivo Assessment of Desloratadine

Testing in animal models with desloratadine confirmed the findings reported from in vitro pharmacology studies and provided in vivo evidence of its antiallergic activity.

In a murine model of inflammation, desloratadine significantly reduced paw swelling following intraplantar histamine injection with an effective dose (ED)50 value of 0.15 mg/kg compared with equivalent amounts of its parent molecule, loratadine.[8] When orally administered, the ED50 for desloratadine was 0.15 mg/kg in conscious guinea pigs receiving a lethal dose of histamine intravenously.[8] Following topical application to the upper airways of guinea pigs, desloratadine potently inhibited histamine-induced increases in microvascular permeability (ED50 value = 0.9µg).[8] In monkeys challenged with histamine, desloratadine at a dose of 6.5 mg/kg significantly inhibited (>90% inhibition) histamine-induced bronchospasm (i.e. increase in pulmonary resistance, decrease in lung compliance).[8]

Animal studies discerned the effect of desloratadine on cough and bronchoconstriction. In ovalbumin-sensitised guinea pigs, desloratadine significantly and dose-dependently reduced the number of coughs induced by aerosolised ovalbumin compared with loratadine.[8] In monkeys naturally allergic to the nematode Ascaris suum, desloratadine therapy significantly reduced airway resistance to 44% compared with 103% for the control group (figure 3).[8] The results of these animal model studies provide evidence that desloratadine is an effective antihistamine worthy of clinical evaluation.

Figure 3.

Comparison of mediator inhibition by the histamine H1-receptor antagonists desloratadine and cetirizine (adapted with permission from Lippert et al. and Blackwell Science[6]). GM-CSF = granulocyte-macrophage colony-stimulating factor; IL = interleukin; TNF = tumour necrosis factor. * p < 0.05 compared with cetirizine.

Desloratadine: Clinical Trials in Seasonal Allergic Rhinitis and Chronic Idiopathic Urticaria

Phase III trials with desloratadine have established its efficacy in reducing the symptoms of SAR and CIU with a rapid onset of action and a durable effect.[31,32] In the SAR studies, desloratadine demonstrated improvement of SAR symptoms, including nasal obstruction, compared with placebo in patients with moderate-to-severe SAR (figure 4).[32,33] Desloratadine reduced both nasal (i.e. rhinorrhoea, nasal obstruction or stuffiness, nasal itching and sneezing) and non-nasal (i.e. itching or burning eyes, tearing or watering eyes, redness of eyes, and itching of ears or palate) symptoms compared with placebo. These effects were sustained for the 24-hour dosing period and the entire 2-week treatment period.[32]

Figure 4.

The effect of desloratadine on allergy symptoms in pivotal clinical trials.[32,33] Effect on seasonal allergic rhinitis (adapted with permission from Meltzer et al.[32]). * p < 0.01 compared with placebo.

Two separate double-blind, placebo-controlled, crossover studies with desloratadine illustrated the potential value of controlled allergen chamber studies.[20,21] The effect of desloratadine on nasal obstruction in asymptomatic patients with at least a 2-year history of SAR was objectively assessed by endoscopy and rhinomanometry-measured nasal airflow. Following exposure[21] and re-exposure[20] to grass pollen in the Vienna Challenge Chamber, patients treated with desloratadine experienced a lower severity of nasal and non-nasal symptoms of systemic AR, including nasal obstruction, compared with placebo (figure 5),[21] with early onset of effect and durable efficacy.

Figure 5.

The effect of desloratadine on nasal obstruction with controlled allergen exposure (reprinted from Horak et al., with permission from Elsevier Science[20]). * p ≤ 0.05, † p ≤ 0.01, ‡ p ≤ 0.001 compared with placebo.

In controlled clinical trials, desloratadine rapidly improved the symptoms of CIU (<24 hours) and provided sustained relief (6 weeks) for patients with moderate-to-severe disease (figure 6).[34,35] Desloratadine reduced pruritus and total symptom scores, as well as the number and size of hives. Treatment with desloratadine resulted in less interference with sleep and daily activities than placebo.[34]

Figure 6.

Effect on chronic idiopathic urticaria (reprinted with permission from Ring et al.[34]). * p < 0.001 compared with placebo.

Large Observational Studies With Desloratadine

Large clinical studies are required by regulatory authorities to verify the efficacy and safety of a drug prior to drug approval. Results of such pivotal clinical trials can be an excellent indicator of the safety and effectiveness of an antihistamine in the treatment of allergic diseases. Because these trials have rigorous study designs, they often include only patients with well defined physical and disease characteristics. Postmarketing surveillance studies provide an opportunity to evaluate the 'real world' profile of a drug under less stringent conditions. These clinical trials employ both objective and subjective measures to demonstrate the rapid and sustained relief of disease symptoms provided by the new antihistamine desloratadine. Data obtained from such observational studies in regular clinical settings can provide confirmation of the efficacy and safety of a drug reported in placebo-controlled studies.

Bachert and colleagues presented data obtained from a large observational study of patients with SAR treated with desloratadine.[36] A total of 48,000 German patients with SAR who met eligibility criteria were included in the study. Patients were monitored regularly by their physicians, and their SAR symptoms were recorded. At the start of the study and upon completion of therapy, patients rated the severity of their nasal, asthma, ocular and dermal symptoms based on a 4-point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe). Quality-of-life parameters, including interference with daily activity and sleep disturbance, were also monitored.

The mean duration of desloratadine therapy was 39 days; compliance with the therapy was rated as good or excellent in 98% of patients. As demonstrated in placebo-controlled studies, desloratadine significantly reduced a wide range of symptoms associated with SAR. The majority of patients also reported a decrease in sleep disturbance caused by SAR and an increase in daily activities. Overall, 92% of patients and 93% of physicians rated the global efficacy of desloratadine as good or excellent. Collectively, the results of this observational study confirmed evidence from many placebo-controlled clinical trials regarding the clinical efficacy and safety of desloratadine in reducing symptoms associated with SAR, including nasal congestion, and in improving patient quality of life.

Recently, a US-wide patient experience programme requested 6000 patients with SAR to describe their most bothersome symptom, other allergy symptoms, and the interference of these symptoms on daily activity.[37] Patients self-rated their symptoms before and after use of desloratadine. Regardless of which was their most bothersome symptom, 85% of patients reported being less bothered following desloratadine therapy. In addition, following desloratadine therapy, patients were bothered less by other allergy symptoms and reported reductions in interference with daily activities.