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

Predicting and Establishing the Clinical Efficacy of a Histamine H

Inhibition of Inflammatory Mediators

Allergic diseases are characterised by activation and subsequent release of inflammatory mediators by immune cells (e.g. mast cells, basophils and T cells). Although histamine is the most abundant mediator present during an allergic response, it is only partially responsible for the symptoms associated with the disease.[2] The allergic cascade involves numerous inflammatory mediators in a complex response that is composed of three distinct immunological phases: sensitisation, early-phase allergic reaction, and late-phase allergic reaction.[2,3]

The sensitisation phase begins with exposure to an allergen and ends with the binding of antigen-specific IgE antibodies on target mast cells.[3]Acute or early-phase allergic reaction begins when IgE-bound mast cells are re-exposed to the allergen in sensitised patients (figure 1).[4] Repeat allergen exposure initiates antigen cross-linking of mast cell-IgE antibodies, causing rapid degranulation of mast cells and release of numerous proinflammatory molecules (e.g. histamine, interleukins, prostaglandins, kinins and leukotrienes). These inflammatory mediators are collectively responsible for increasing local blood flow and vascular permeability, stimulating excessive secretion of mucus, and reducing airway patency in both upper and lower respiratory mucosal tissues. The clinical outcome is a rapid onset of sneezing, itching, rhinorrhoea and nasal obstruction in affected patients (figure 1).[2,3]

Figure 1.

The mechanism and chemical mediators of the type-1 allergic reaction (adapted with permission from Baena-Cagnani[4]). ICAM = intercellular adhesion molecule; IgE = immunoglobulin E; IL = interleukin; LTC = leukotriene C; PGD = prostaglandin D; RANTES = Regulated on Activation, Normal T cell Expressed and Secreted; TNF = tumour necrosis factor

Late-phase allergic reactions are noted approximately 4-6 hours following the early-phase reaction and are characterised as a cellular inflammatory response (figure 1).[2] This response results in the accumulation of inflammatory granulocytes, predominantly eosinophils, and chemoattractants (e.g. RANTES [Regulated on Activation, Normal T cell Expressed and Secreted], eotaxin), and the generation of cytokines (e.g. interleukin [IL]-5) by granulocytes or lymphocytes in the respiratory mucosa. Cellular adhesion molecules (e.g. intracellular adhesion molecule 1) permit inflammatory cells to traverse the endothelium and enter airway tissues.[5] The accumulation of eosinophils and subsequent release of eosinophil-derived chemical mediators establishes the late-phase allergic responses of nasal obstruction, increased mucus production, and possibly, hyper-responsiveness.[3] Basophil-mediated histamine and cytokine release appears to play a subordinate role during the late-phase reaction.[2] Clinical manifestations of this phase can include those of the early-phase response, but nasal obstruction and increased mucus production are most commonly observed.

In vitro studies have been useful in predicting the clinical efficacy of an antihistamine by assessing its ability to block allergic inflammatory processes. The ability of an H1-receptor antagonist not only to block the H1 receptor, but also to inhibit the generation and release of histamine and other inflammatory mediators and prevent the migration and accumulation of inflammatory cells, contributes to its antiallergic activity. In vitro analysis has demonstrated that among currently available second-generation agents, this ability varies widely.[6,7]

Affinity and Specificity for H1-Receptor Antagonists: In Vitro Analysis

Unquestionably, histamine is a major contributor in the pathophysiology of allergic conditions.[8] Following release from mast cells and basophils, the allergic effects of histamine are mediated through activation of the multiple H1 receptors found on blood vessels, airway, cardiac myocytes, and cells of the central nervous system.[9] The H1 receptor appears to play a predominant role in IgE-mediated allergic conditions because perturbation of this receptor leads to tissue responses and symptoms of allergic rhinitis and urticaria.[8]

The binding characteristics of an H1-receptor antagonist determine the extent to which histamine can be blocked from binding to the H1 receptor; these binding characteristics are also integral to the efficacy and safety of an antihistamine. In theory, the binding of an antagonist to H1 receptors on target cells should inhibit all effects of histamine.[9] However, specific characteristics of an H1-receptor antagonist may influence its potency. Some antagonists may bind to the H1 receptor in a reversible fashion, thereby leading to more transient effects.[10] Nonselective H1-receptor antagonists may lack specificity and bind to other receptors for histamine, serotonin and bradykinin, and cause unwanted anticholinergic effects.[11]

Receptor-binding studies have revealed a number of important differences among available antihistamines. First-generation antihistamines rapidly dissociate from H1-receptor sites, which contributes to their short duration of action. Furthermore, many first-generation agents lack specificity for the H1 receptor; some of these agents also bind to cholinergic (muscarinic) receptors and commonly cause dry mouth, tachycardia and constipation.[9] In contrast, select second-generation antihistamines exhibit noncompetitive antagonism for the H1 receptor and have slow dissociation; this characteristic may explain their sustained efficacy observed in clinical trials.[12,13] Some second-generation antihistamines cross the blood-brain barrier and are associated with sedation, while other antihistamines of this class have improved receptor specificity, which reduces the potential for adverse reactions.[14] However, high in vitro H1-binding potency does not necessarily imply good clinical efficacy because many other factors (e.g. uptake, metabolism and pharmacokinetics) are also relevant.

Recently, Leurs and colleagues proposed a novel concept referred to as inverse agonism to describe the interaction between histamine and its cognate receptor.[15] In this model, binding of histamine (i.e. agonist) to its receptor shifts the equilibrium of the receptor from an inactive to an active state. Any molecule that binds to the receptor (e.g. antihistamines) and stabilises the inactive confirmation would be referred to as an inverse agonist . Although this definition has not been used to redefine current antihistamines, the authors propose that because of their mechanisms of action, antihistamines should be termed inverse agonists because binding to the H1 receptor stabilises the inactive conformation and ultimately downregulates receptor activity in the absence of an agonist.[15]

Animal Studies: In Vivo Analysis

Animal models permit the investigation of an antihistamine in an in vivo setting. They provide additional preclinical evidence of antiallergic and antihistaminic activity. Antiallergic effects are commonly assessed using sensitised guinea pigs or allergic monkeys; antihistaminic effects are often evaluated in the mouse-paw model. It is important to note that while animal models can provide invaluable insight into the efficacy and safety of a particular therapy, the results obtained may not correlate with what is observed in humans due to intrinsic species variability.

Histamine-Induced Skin Wheal-and-Flare Model

The histamine-induced skin wheal-and-flare model has been widely used,[16] but has several limitations. Although histamine is a well recognised mediator of an allergic response, a true allergic reaction results from a multitude of interactions among numerous cells and mediators. The wheal-and-flare response following histamine injection mimics the early phase of the allergic reaction, but there is no mast cell degranulation or inflammatory mediator release and the late-phase response is lacking.[16] Considerable variability has been reported in the activity of available antihistamines in the histamine-induced wheal-and-flare model, and data often do not correlate with results from clinical studies in patients with symptomatic allergic diseases.[17,18,19] As such, the clinical effectiveness of an antihistamine may not necessarily be accurately predicted.

Allergen Chamber Studies: Controlled in Vivo Experience

Large, well designed, placebo-controlled, prospective clinical trials provide the best indication of the efficacy of an antihistamine (see Pivotal Clinical Trials ). Findings from such clinical trials may be limited because certain factors cannot be readily controlled. These factors can include weather conditions, annual and diurnal variation in pollen levels, and antigenic variability of pollens of similar species. Allergen chamber studies allow the effects of an antihistamine on a specific allergic disease to be followed under controlled conditions over time. Recently, allergen chamber studies have been used to test the onset of action, duration of effect, and the efficacy of antihistamines in reducing the symptoms of allergic rhinitis during allergen exposure.[20,21] Under these controlled conditions, antihistamines rapidly improve and reduce symptoms of allergic rhinitis.[20] Although this type of clinical study is often limited in the size of the patient population, and symptom severity is rated by subjective scales, it does provide additional evidence of the clinical activity of an antihistamine.

Pivotal Clinical Trials

Pivotal clinical trials are typically large, multicentre, prospective, randomised, double blind, parallel group and placebo controlled in design. Clinical trials are the best indicator of the effectiveness, safety and tolerability of an antihistamine in the treatment of allergic diseases. In contrast to controlled allergen chamber studies, exposure to an allergen in pivotal clinical trials involves natural environmental exposure in the clinical practice setting (i.e. fall and spring allergy seasons). Clinical studies allow for the assessment of long-term (≥6 weeks) therapy on symptom reduction. They also permit testing in a broad patient population under conditions that approximate the clinical practice setting. Patient assessments are standardised, and statistical analysis of data provides scientifically meaningful information for establishing the efficacy of an agent.

Clinical trials with antihistamines have been used to test their efficacy and safety in a range of diseases, including SAR, PAR and CIU. Pivotal trials of patients with CIU allow for assessment of the clinical efficacy of an antihistamine in a broad patient population over a longer period of time and are more likely to capture all stages of this relapsing disease. Pivotal clinical trials for this disease generally focus on symptom abatement, thus providing results that accurately reflect the ability of an antihistamine to inhibit the systemic allergic process.

The final arbiter of the clinical usefulness of a drug in the 'real world' is postmarketing surveillance studies. These studies provide two key beneficial effects not found in phase III clinical studies: (i) the beneficial effects possibly due to close monitoring of patients are no longer apparent, and (ii) the patients selected are from a 'real-life' setting and not the highly selected patients who are enrolled in clinical trials.

Accurately assessing the clinical efficacy and safety of antihistamines is a multimodal paradigm, which begins with studies evaluating in vitro binding and concludes with large postmarketing surveillance studies. In the following section, the various methods used to evaluate antihistamines illustrate the developmental process for evaluating the efficacy of the H1-receptor antagonist desloratadine. Preclinical and clinical data on desloratadine will be presented and discussed to illustrate its antihistaminic, antiallergic and anti-inflammatory properties, as well as its clinical efficacy in treating allergic conditions such as SAR and CIU.