Safety Profile of Bilastine: 2Nd Generation H1-Antihistamines
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European Review for Medical and Pharmacological Sciences 2012; 16: 1999-2005 Safety profile of Bilastine: 2nd generation h1-antihistamines F. SCAGLIONE Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy Abstract. – Bilastine is a new H1 antagonist with Drugs that bind to H1-receptors and act as in- no sedative side effects, no cardiotoxic effects, and verse agonists, reduce allergic inflammation di- no hepatic metabolism. In addition, bilastine has rectly through the H1-receptor by interfering proved to be effective for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria. with histamine action at H1-receptors, either on Pharmacological studies have shown that bi- sensory neurons or on small blood vessels. In- lastine is highly selective for the H1 receptor in volving the ubiquitous transcription factor nu- both in vivo and in vitro studies, and with no ap- clear factor-kB, they also decrease expression of parent affinity for other receptors. The absorp- proinflammatory cytokines, cell adhesion mole- tion of bilastine is fast, linear and dose-propor- cules and chemotaxis10,11. tional; it appears to be safe and well tolerated at However, through the H1-receptor, histamine all doses levels in healthy population. Multiple administration of bilastine has confirmed the contributes to regulation of cell proliferation and linearity of the kinetic parameters. The distribu- differentiation, hematopoiesis, embryonic devel- tion in the brain is undetectable. The safety pro- opment, regeneration, and wound healing and file in terms of adverse effects is very similar to plays an important role in neurotransmission in placebo in all Phase I, II and III clinical trials. Bi- the central nervous system (CNS). It has anticon- lastine (20 mg), unlike cetirizine, does not in- vulsant activity and contributes to regulation of crease alcohol effects on the CNS. Bilastine 20 mg does not increase the CNS depressant effect vigilance (alertness and attention), cognition, of lorazepam. Bilastine 20 mg is similar to place- learning, memory, and the circadian sleep-wake bo in the driving test. Therefore, it meets the cur- cycle, as well as to energy and endocrine home- rent criteria for medication used in the treatment ostasis12. of allergic rhinitis and urticaria. Since histamine trough the H1-receptor exerts many functions, it appear that drugs blocking this Key Words: receptor in all body including CNS, may have H(1)-antihistamine, Bilastine. many side effects beside its beneficial effects. H1-antihistamines are functionally classified into 2 groups. First-generation medications readi- Introduction ly cross the blood-brain barrier (BBB) and occu- py H1-receptors located on postsynaptic mem- Although histamine exerts important physio- branes of histaminergic neurons throughout the logic functions in human health through 4 sub- CNS. Second generation H1-antihistamines do types of receptors1-5, it is the activity at H1 hista- not cross the BBB readily6. mine receptors that is involved in allergic reac- First-generation antihistamines are effective in tions6. controlling allergic rhinitis symptoms, but they Histamine plays an important role in the are also associated with side effects such as seda- pathophysiology of allergic disorders, including tion and antimuscarinic effects12,13. These side ef- allergic rhinitis and urticaria7,8. fects may interfere with daily activities and in- Through the H1-receptor, histamine increases crease the risk of accidents in situations such as release of some mediators from mast cells and driving or operating machinery, where high lev- basophils, downregulates humoral immunity, in- els of alertness are required. Furthermore, they creases antigen-presenting cell capacity and up- are likely to reduce compliance because of exces- regulates TH1 priming and proliferation, IFN- sive fatigue and malaise. For these reasons were production, cellular adhesion molecule expres- practically abandoned as anti allergic drugs. sion, and chemotaxis of eosinophils and neu- Second-generation H1 receptor antagonists trophils9. have largely superseded their first-generation Corresponding Author: Francesco Scaglione, MD; e-mail: [email protected] 1999 F. Scaglione counterparts, owing to more favourable pharma- it does not interact with cytochrome P450. There- cokinetics and reduced (or negligible) sedative fore, it meets the current European Academy of effects. The most frequently used second-genera- Allergy and Clinical Immunology (EAACI) and tion H1-receptor antagonists are desloratadine, Allergic Rhinitis and its Impact of Asthma loratadine, fexofenadine, cetirizine, levocetirizine (ARIA) criteria for medication used in the treat- and bilastine. ment of allergic rhinitis21. Bilastine was approved Second-generation antihistamines are less se- for use in the European Union in 201022, and is dating than the first generation agents for their currently being introduced into clinical practice limited penetration across the blood-brain in 28 Countries of the European Union (EU) for barrier6,14, and a major reason for this is thought the symptomatic treatment of allergic rhinocon- to be P-glycoprotein-mediated efflux of the drug junctivitis (perennial and seasonal) and urticaria from the CNS15,16, but also for their less lipid sol- in adults and children over 12 years. ubility than the first-generation agents17. In addi- tion, these new-generation agents are more selec- Pharmacological Profile tive for H1 receptors and, hence, are not associat- Pharmacological studies have shown that bi- ed with adverse events arising from interactions lastine is highly selective for the H1-receptor in at other receptor types6. Finally, their drug-drug, both in vivo and in vitro studies, and with no ap- drug-food, and drug–herbal product interactions, parent affinity for other receptors. if any, are less clinically relevant14. These preclinical studies provide evidence that The main purpose of this report is to evaluate bilastine has H1-antihistamine activity, with high the safety profile of bilastine, the most recent specificity for H1-receptors, and poor or no affin- second-generation H1-receptor antagonists intro- ity for other receptors such as serotonin, duced in clinical practice. The clinical efficacy of bradykinin, leukotriene D4, calcium, muscarinic bilastine has recently been assessed18, for which M3-receptors, alpha1-adrenoceptors, beta2- will not be extensively evaluated in this report. adrenoceptors, and H2- and H3-receptors. More- over, in the in vitro Schultz-Dale reaction bilas- Bilastine tine demonstrated anti-inflammatory activity23. Bilastine is a new antihistamine that is not In vivo preclinical studies confirmed those ob- structurally derived from any antihistamines cur- tained from previously conducted in vitro experi- rently on market, nor is it an active metabolite or ments of bilastine, and provide evidence that bi- enantiomer of another antihistamine. From a lastine possesses antihistaminic as well as antial- structural point of view is 2-[4-(2-(4-(1-(2- lergic properties, with similar potency to ceti- ethoxyethyl)-1Hbenzimidazol-2-yl)piperidin-1- rizine and superior potency to fexofenadine24. yl)ethyl)phenyl]-2-methyl propionic acid, with a molecular weight of 463.6 daltons and a chemi- Pharmacokinetics cal structure similar to piperidinyl-benzimidazole Bilastine, studied in single- and multiple-dose (Figure 1)19,20. This chemical structure, with the trials in healthy volunteers, presents linear phar- hydrophilic carboxylic substituent, contributes to macokinetics with regard to maximum plasma the low penetration into CNS. Bilastine is a po- concentration (Cmax) and area under the plasma tent, effective, non-sedating antihistamine, with- concentration-time curve (AUC) in the dose out cardiac toxicity, absence of metabolism, and range studied (2.5 to 220 mg), with a low in- terindividual variability. The drug is rapidly ab- sorbed after oral administration with a time to Hydrophilic maximum plasma concentration of around 1 moiety hour. No drug accumulation was observed with repeated bilastine administration. The mean val- ue of bilastine oral bioavailability was found about 61%24. In a population pharmacokinetic model the predicted median value for Cmax was 220 ng/mL, and the apparent volume of distribu- tion was 59.2 L for the central compartment and Figure 1. Chemical structure of Bilastine. The hydrophilic 30.2 L for the peripheral compartment. At thera- carboxylic substituent, contribute to the low penetration into peutic doses bilastine is 84-90% bound to plasma CNS. proteins25,26, and the mean AUC from time zero 2000 Safety profile of Bilastine: 2nd generation H1-antihistamines to 24 hours was 990 ngh/mL after a single 20 mg The type and frequency of adverse events, tol- dose of bilastine in 48 healthy volunteers27. erability, and general safety of treatment were Bilastine is a substrate of P-glycoprotein (P-gp) evaluated in all clinical trials. and organic anion transporter inhibitor (OATP)- Bilastine was generally well tolerated in pa- 1A212,13. Bilastine does not appear to be a substrate tients with seasonal or perennial allergic rhinitis of the transporter BCRP or renal transporters or chronic urticaria34-37. OCT2, OAT1 and OAT3. Based on in vitro studies, The overall prevalence of treatment-related ad- bilastine is not expected to inhibit the following verse events was 15-30% and 19-28% in bilastine transporters in the systemic circulation: P-gp,