Bilastine, a novel new-generation antihistamine that is highly selective for the H1 histamine receptor, has a rapid onset and prolonged duration of action. This agent does not interact with the cytochrome P system and does not undergo significant metabolism in humans, suggesting that it has very low potential for drug—drug interactions, and does not require dose adjustment in renal impairment.
Bilastine has demonstrated similar efficacy to cetirizine and desloratadine in patients with seasonal allergic rhinitis and, in a Vienna Chamber study, a potentially longer duration of action than fexofenadine in patients with asymptomatic seasonal allergic rhinitis.
It has also shown significant efficacy similar to that of cetirizine and safety in the long-term treatment of perennial allergic rhinitis.
The fourfold higher than standard dose is specified as an acceptable second-line treatment option for urticaria in international guidelines.
Bilastine is generally well tolerated, both at standard and at supratherapeutic doses, appears to have less sedative potential than other second-generation antihistamines, and has no cardiotoxicity.
Based on its pharmacokinetic properties, efficacy, and tolerability profile, bilastine will be valuable in the management of allergic rhinitis and urticaria. Introduction The frequency and impact of allergic diseases are often underestimated. No date limits were applied. All preclinical and clinical trials were assessed for inclusion in the review. Attention was preferentially given to randomized controlled trials, with appropriate controls for variation and bias eg, placebo group, blinding.
Burden of allergic diseases in Asia Pacific Allergic rhinitis Allergic rhinitis is a symptomatic condition of the nose caused by allergen exposure and IgE-mediated inflammation.
Allergic rhinitis is frequently encountered in primary care. Patients report that allergic rhinitis has a marked detrimental effect on their sleep, social life, quality of life, and attendance and functioning at school and work. Considerable clinical and epidemiological evidence also exists of an association between asthma and allergic rhinitis.
Patients with urticaria typically develop wheals hives , angioedema, or both. Symptoms of the disorder may endure for several months or years. The consequence is a series of intracellular reactions culminating in exocytosis and the release of histamine and other inflammatory mediators such as platelet-activating factor and cytokines. H1, H2, H3, and H4. These are G-protein-coupled receptors that transfer extracellular signals via G proteins, which act as intermediaries between cell surface receptors and intracellular second messengers Figure 1.
Figure 1 Intracellular signaling processes mediated by G-proteins after interaction of histamine with each receptor subtype. H1 receptors are ubiquitous and are found in the adrenal medulla, CNS, endothelial and epithelial cells, heart, immune cells, sensory nerves, and smooth muscle. Outcomes include pruritus, sneezing, increased vascular permeability, and edema.
History of antihistamines Histamine was discovered in by Windaus and Vogt, after decarboxylation of the amino acid histidine. More specifically, this was for his discoveries that synthesized agents that inhibited the actions of various body substances, particularly on the vascular and musculoskeletal systems.
These agents represented a major enhancement in antihistamine development because they had no or only minimal sedative activity. Such cardiotoxic potential is now well established and has been extensively reviewed. Further modifications then led to the introduction of other second-generation agents: A recent development is the dual platelet activator factor and histamine H1 receptor antagonist rupatadine, 43 which undergoes extensive hepatic metabolism to produce active metabolites, including desloratadine.
Fundamental among these properties are potent and selective blocking activity at H1 receptors, a rapid onset and long duration of action, efficacy in allergic rhinoconjunctivitis, and against all symptoms, including nasal obstruction, no interaction with cytochrome P CYP , no sedative activity or cognitive or psychomotor impairment, no anticholinergic activity, no cardiac safety concerns, and no potential for tachyphylaxis.
As outlined in the following sections, bilastine — as a modern, second-generation H1 antihistamine — has the highest number of desired features for a modern antihistamine according to international ARIA guidelines Table 2.
Table 2 Clinical profile differences between various second-generation H1 antihistaminesa Notes: If efficacy is confirmed, and no major safety or toxicity concerns are identified, progression can continue to phase I clinical studies in healthy volunteers and then to Phase II—III clinical trials in the proposed indication.
With novel antihistamines eg, bilastine , a specific goal of in vitro studies is to confirm that the test agent has marked selectivity — high affinity for histamine H1 receptors, but minimal effects at receptors for other mediators and amines. In in vivo studies, bilastine showed antihistaminic activity in various animal models and produced the following effects: Specifically, bilastine reduced vascular permeability mediated by passive cutaneous anaphylaxis in rats and reduced IgG-dependent active cutaneous anaphylaxis.
In mice, bilastine reduced IgE-dependent active cutaneous anaphylaxis and the passive Arthus reaction induced by ovine red blood cells. Reproduced from Clin Pharmacokinet, Pharmacokinetic-pharmacodynamic modelling of the antihistaminic H1 effect of bilastine, ; However, some oral H1 antihistamines eg, loratadine, rupatadine are extensively transformed to active metabolites by the CYP system in the liver. This creates significant potential for drug—drug interactions. Oral bilastine can be administered to patients independently of glomerular filtration rate.
These transporters have a significant influence on the pharmacokinetic profile of various drugs since P-gP can be considered as an efflux pump, whereas organic anion-transporter proteins can facilitate drug uptake. Further research in this area is clearly warranted. Indeed, transporter protein interactions might ultimately explain important clinical differences, such as the potentially longer duration of action for bilastine over fexofenadine.
Seasonal allergic rhinitis In two multicenter, randomized, double-blind, placebo-controlled trials in a total of 1, patients with seasonal allergic rhinitis, the efficacy of bilastine was compared with that of cetirizine 57 and desloratadine.
The same was true for NNSS for ocular tearing, redness, and itching: Data from Kuna et al. In the other trial, 58 similar results to the first study were obtained for bilastine and desloratadine versus placebo over a 2-week treatment period. Data from Horak et al. TNSS, total nasal symptom score. Bilastine is indicated for allergic rhinoconjunctivitis, whereas not all antihistamines have this specific indication Table 2.
Conversely, no significant difference was evident in South Africa, where patients reported a relatively high placebo response rate. Comparison of the efficacy and safety of bilastine 20 mg vs levocetirizine 5 mg for the treatment of chronic idiopathic urticaria: TSS, total symptom score. Bilastine is more effective than cetirizine at limiting the early allergic response, according to the results of a study in volunteers.
Bilastine has been evaluated at a range of doses, from the recommended dose of 20 mg to four times this dosage ie, 80 mg once daily in a randomized, double-blind, placebo-controlled, 7-day study in patients with acquired cold urticaria. Further research is needed to demonstrate its efficacy in other inducible forms of urticaria, which may include urticaria induced by pressure, heat, sun exposure, exercise, or contact with specific allergens.
The use of supratherapeutic doses of bilastine in the study of patients with cold urticaria is consistent with international guideline recommendations.
For instance, the sedative potential of cetirizine, desloratadine, and loratadine will likely be markedly greater than that of bilastine, fexofenadine, and levocetirizine. Bilastine doses of 20 mg and mg had no clinically significant effect on QTc interval. Bilastine 20 mg was also administered with ketoconazole and had no effect on QTc interval when used in combination. Comparative efficacy of non-sedating antihistamine updosing in patients with chronic urticaria.
World Allergy Organ J. Headache and dizziness showed a similar incidence between all active treatment and placebo groups. Somnolence occurred with a similar frequency in bilastine 3.
However, cetirizine was associated with a significantly greater incidence of somnolence 7. Based on published data for other agents, it appears that bilastine has the lowest rate of brain H1 receptor occupancy of all the available antihistamines Table 3. Table 3 Percentage of brain H1 receptor occupancy mean after oral administration of antihistamines using PET 67 , 69 — 73 Abbreviation: PET, positron emission tomography.
This study showed no significant effect on QTc interval using these stringent criteria. For registration of the adult formulation of bilastine, the clinical plan was developed to comply with the European Medicines Agency guidelines and therefore the cut off age is 12 years.
However, bilastine has been investigated according to a Paediatric Investigation Plan that was designed according to the requirements of the European Medicines Agency Paediatric Committee. Publication of data from the Paediatric Investigation Plan is awaited with interest. Conclusion Currently, there are a number of unmet needs in the management of allergic conditions in Asia Pacific, 14 , 75 with many patients still experiencing sedation from the use of older antihistamines.
Acknowledgments The authors would like to acknowledge Menarini Asia-Pacific Holdings Pte Ltd for providing logistic support and funding for the consensus meeting and for commissioning MIMS Pte Ltd to provide writing assistance and editorial support. The views expressed in this manuscript are solely those of the authors.
Disclosure The authors report no conflicts of interest in this work.