Bilastine in Allergic Rhinoconjunctivitis and Urticaria C

REVIEW ARTICLE Bilastine in allergic rhinoconjunctivitis and urticaria C. Bachert1, P. Kuna2 & T. Zuberbier3

1Department of Otorhinolaryngology, University Hospital Ghent, Ghent, Belgium; 2Division of Internal Medicine, Asthma and Allergy, Berlicki University Hospital, Lo´ dz, Poland; 3Department of Dermatology and Allergy, Charite´ -Universita¨tsmedizin Berlin, Germany

To cite this article: Bachert C, Kuna P, Zuberbier T. Bilastine in allergic rhinoconjunctivitis and urticaria. Allergy 2010; 65 (Suppl. 93): 1–13.

Keywords Abstract allergic rhinoconjunctivitis; anti-allergic Allergic rhinoconjunctivitis and urticaria are increasing in prevalence in many devel- antihistamines; bilastine; H1-receptor antagonists; urticaria. oped countries. The role of histamine in such conditions is well documented and clinical guidelines recommend non-sedating H1-receptor antagonists as ﬁrst-line Correspondence treatment choices. Bilastine is a novel non-sedating histamine H1-receptor antago- C. Bachert, Department of nist developed for the treatment of allergic rhinoconjunctivitis and urticaria. The Otorhinolaryngology, University Hospital aim of this review is to critique the scientiﬁc evidence relating to the pharmacologi- Ghent, Ghent, Belgium. cal properties of bilastine and the clinical evidence regarding its potential as an anti- Tel.: 09 332 2332 histamine. In vitro binding studies and investigations in animal tissue have

Fax: 09 332 4993 demonstrated the high specificity of bilastine for H1-receptors, and preclinical ani- E-mail: [email protected] mal studies have also yielded promising results in terms of a reduction of histamine- mediated inflammatory effects, including capillary permeability and bronchospasm. Accepted for publication 13 April 2010 In pharmacodynamic studies bilastine was found to down-regulate histamine- induced flare and wheal responses in healthy volunteers. Preclinical and clinical DOI:10.1111/j.1398-9995.2010.02404.x pharmacokinetic studies showed that bilastine has dose-dependent kinetics following oral administration. Excretion is almost exclusively via urine and faeces as unchanged drug. Early clinical trials have shown that bilastine has similar efficacy

to other second-generation H1-receptor antagonists such as cetirizine, desloratadine, fexofenadine and levocetirizine, in terms of reducing allergic symptoms. Clinical findings also indicate that bilastine has a rapid onset of action and a 20 mg single dose is effective throughout a 24-h period. Furthermore, bilastine has been associated with improved quality of life in allergic rhinoconjunctivitis and urticaria patients. Adverse effects have generally been minimal in these studies and doses up to twice those proposed did not exhibit differences in adverse events compared to placebo. Moreover, in vivo investigations have found no evidence of accumulation of bilastine in the central nervous system, and various studies have confirmed minimal effects on psychomotor performance in healthy volunteers administered up to four times the usual dose. Clinical studies have also found no effect of bilastine on the QTc interval and other ECG parameters, even at supratherapeutic dosages, confirming the good cardiac safety profile of this newer antihistamine. Given its pharmacodynamic profile, which appears to be similar to other second-generation

H1-receptor antagonists, and its favourable safety and tolerability, bilastine has the attributes of a potentially clinically useful non-sedating antihistamine. Larger clinical studies are now necessary to fully elucidate the clinical potential of this novel antihistamine.

Diseases such as allergic rhinoconjunctivitis and urticaria are gent theories. The ﬁrst suggests that reduced exposure to becoming increasingly prevalent in many developed countries allergens during childhood increases the risk of allergy and is (1–3). Estimates suggest that approximately 10–40% of the referred to as the ‘hygiene hypothesis’ (9). In contrast, the global population is affected by allergic rhinoconjunctivitis ‘pollution hypothesis’ proposes that the risk of developing (4–7). The prevalence of urticaria is similar, with a lifetime allergic diseases is potentiated by atmospheric pollution (10). incidence of approximately 20% (8). The reasons for the The impact of these diseases on the patient’s quality of life increased prevalence of allergic diseases are largely unex- (QoL) can be signiﬁcant as a result of loss of sleep and fati- plained, although potential causes are proposed by two diver- gue, headache, irritability and the inability to concentrate.

Allergy 65 (Suppl. 93) (2010) 1–13 ª 2010 John Wiley & Sons A/S 1 Bilastine in allergic rhinoconjunctivitis and urticaria Bachert et al.

Such symptoms can ultimately impair performance in school Table 1 Allergic Rhinitis and its Impact on Asthma (ARIA) classifi- and the workplace (7, 11, 12). Given the high prevalence of cation system for allergic rhinoconjunctivitis (21) allergic rhinoconjunctivitis in particular, the costs to society Classification Definition can be extremely high, with estimates suggesting that indirect costs due to loss of productivity are greater than those Intermittent allergic Symptoms are present for <4 days a incurred for providing healthcare to this patient group (13). rhinoconjunctivitis week or <4 weeks. Thus, development of effective treatments should not only Persistent allergic Symptoms are present for >4 days a provide symptomatic relief and increase the QoL of the rhinoconjunctivitis week and for >4 consecutive weeks. patient, they should also improve individual performance, Mild allergic No impairment of sleep, daily reduce clinic visits and increase productivity. The benefits for rhinoconjunctivitis activities, sport or leisure, work or overburdened healthcare systems and resources, and society school and no disruptive symptoms. in general, are potentially enormous (13). Moderate to severe Presence of one of the following The role of histamine in allergic diseases is well described allergic rhinitis events: abnormal sleep, impairment in the literature (14–16). In brief, immunoglobulin E (IgE) of daily activities, sport or leisure; antibodies are recognised at the surface of mast cells and on impaired work or school; or disruptive exposure to the appropriate antigen following an allergic symptoms. stimulus, trigger the release of histamine via mast cell degranulation. Histamine mediates its effects via activity at several receptors including the H1-, H2-, H3- and H4- receptors. Bio- and lower respiratory tract infection, emphasising the impor- logical effects of histamine involved in allergic reactions are tance of effective treatment for this patient population. related to activity at H1-receptors and include smooth muscle The term urticaria refers to: physical urticarias, acute urti- contraction, bronchospasm, increased endothelial permeabil- caria, chronic ‘idiopathic’ urticaria, and urticarial vasculitis, ity and stimulation of sensory nerves and cough receptors defined by spontaneously occurring wheals and/or angioe- (17). Therefore, treatments blocking the effects of histamine dema (24, 25). Wheals are characterised by central swelling at H1-receptors (antihistamines) play a vital role in the man- of variable size, associated itching or burning and are gener- agement of diseases including allergic rhinoconjunctivitis and ally fleeting in nature; the skin usually recovers within 24 h urticaria. (26). Angioedema has a slower resolution and is associated Allergic rhinoconjunctivitis is a chronic respiratory illness, with swelling of the lower dermis and subcutis, pain rather characterised by rhinorrhoea, nasal congestion, sneezing and than itching and involvement of mucous membranes. Differ- nasal itch, and is often accompanied by lacrimation, ocular ent types of urticaria are associated with a common, complex redness and itching of the ears and palate (11). Histamine is pathogenesis, involving increased cytokine expression, an important mediator of these symptoms although other oedema, leukocyte infiltration to the perivascular space, and mediators including leukotrienes, prostaglandins and kinins mast cell degranulation (26–29). These varied effects are contribute to pro-inflammatory cellular effects, such as up- indicative of a multi-factorial process involving many media- regulation of endothelial and epithelial adhesion molecules, tors, in addition to mast cell-induced production of hista- cytokines and chemokines and activation of leukocytes (6, mine. EAACI/GA2LEN/EDF/WAO guidelines for the 18, 19). Allergic rhinoconjunctivitis has traditionally been management of urticaria recommend avoidance of allergic categorised into seasonal and perennial allergic rhinocon- stimuli and treatment with non-sedating H1-receptor antago- junctivitis, mainly based on the time of exposure. Seasonal nists (26, 30, 31). In non-responding patients, higher doses allergic rhinoconjunctivitis (SAR) is associated with a wide (up to 4-fold) are recommended. For this reason and as daily variety of pollen allergens and thus is dependent upon geo- drug administration may be required for longer periods graphic location and time of year, whereas perennial allergic (weeks to years), H1-receptor antagonists must have a good rhinoconjunctivitis (PAR) is most frequently caused by pol- tolerability profile (32). lens, mites and/or animal dander (6). However, there are Several national and international clinical guidelines have exceptions to both categories and thus the Allergic Rhinitis recommended that H1-receptor antagonists should be and its Impact on Asthma (ARIA) workshop, in conjunc- regarded as the first-line treatment for allergic rhinoconjunc- tion with the WHO, introduced a new classification for tivitis (4, 6, 11, 33, 34) and urticaria (26, 31). First-generation allergic rhinoconjunctivitis, based on duration and severity antihistamines were defined by their ability to antagonise of symptoms (4, 20, 21) (Table 1). The ARIA classification H1-receptors and thereby effectively control allergic symp- recognises allergic rhinoconjunctivitis as a chronic respira- toms. However, they were frequently associated with adverse tory illness and provides guidance which may aid treatment. events, especially sedation. This led to development of

This is important given that allergic rhinoconjunctivitis is second-generation H1-antihistamines, which were designed to one of the top ten reasons for patients visiting their general be less lipophilic so as to minimise transfer across the blood- practitioner (22). Indeed, a two-step, cross-sectional, popula- brain barrier and thus avoid producing sedative effects. The tion-based survey reported a mean incidence of 23% (range ultimate goal was to improve the therapeutic index, but some

17–29%) in six European countries (23). Furthermore, aller- second-generation H1-receptor antagonists have been associ- gic rhinoconjunctivitis is often associated with other respira- ated with adverse effects such as weight gain, drug-drug tory conditions including asthma, sinusitis, nasal polyposis interactions and of most concern, potentially life threatening

2 Allergy 65 (Suppl. 93) (2010) 1–13 ª 2010 John Wiley & Sons A/S Bachert et al. Bilastine in allergic rhinoconjunctivitis and urticaria

and non-competitive antagonistic properties from 100 nM. Bilastine was approximately 5.5 times more potent than cetirizine as a competitive antagonist and 10 times more potent than cetirizine as a non-competitive antagonist. In guinea pig tracheal preparations, bilastine exhibited non-competitive antagonism (Table 2). Interestingly, in guinea pig ileum bilas-

tine demonstrated a residual effect as H1-receptors did not recover contractile activity to histamine following several washes (17). Figure 1 Chemical structure of bilastine. Additional isolated organ studies conﬁrmed the speciﬁcity

of bilastine for H1-receptors compared with other histamine receptor subtypes. For example, it did not alter the positive cardiotoxicity (2). Bilastine, F-96221-BM1, 2(2-[4-(2-(4-(1-(2- chronotropic effect of the H2-agonist dimaprit in guinea pig ethoxyethyl) bencimidazole-2-yl) piperidine-1-yl) ethyl) phe- right atria and responses to bilastine on electrical twitches in nyl]-2-methylpropanoic acid) (Fig. 1), is a novel non-sedating guinea pig jejunum were considered to be unrelated to activ- histamine H -receptor antagonist developed for the treatment 1 ity at H3 receptors. Furthermore, bilastine 10 lM did not of allergic rhinoconjunctivitis and urticaria. The aim of this inhibit the specific binding of [3H]-histamine to human review is to critique the current literature relating to the recombinant histamine H4-receptors stably transfected and pharmacological properties of bilastine and to evaluate the expressed in HEK-293 cells (17). preliminary scientific evidence regarding its clinical efficacy The effects of bilastine at a variety of other receptor types and safety. were investigated using in vitro methods. Radioligand binding studies assessed the specificity of bilastine for a range of 30 Preclinical and clinical pharmacology different receptors including serotonin, bradykinin, leukotriene, calcium, muscarinic and adrenergic receptors. No signifi- The preclinical pharmacology of bilastine was presented in cant displacement of other radioligands was found with detail by Corco´stegui et al. (17) and the main findings are bilastine at a concentration of 10 lM. Indeed, bilastine at summarised below. this concentration demonstrated no significant anti-muscarinic activity in C6 rat glioma cell lines expressing one of the Preclinical: in vitro studies five human muscarinic receptors (M1–M5) (35). Studies in guinea pig ileum are consistent with a lack of effect at musca- In vitro radioligand-receptor binding studies have clearly rinic receptors as bilastine did not alter M3-mediated contrac- demonstrated the affinity of bilastine for histamine H1-recep- tion (17). 3 tors. Bilastine inhibited binding of [H ]-pyrilamine in a dose- Findings from several isolated organ experiments using dependent manner in guinea pig cerebellum and human high concentrations of bilastine further confirmed bilastine embryonic kidney (HEK)-293 cells expressing human recom- as a selective H1-receptor antagonist. Thus, bilastine at a binant H1-receptors. A mean affinity value (Ki) for bilastine concentration of 10 lM or higher, did not modify the con- of 64 nM was calculated in the HEK-293 cell line. This was centration-response curves induced by serotonin, bradyki- similar to the mean value calculated in H1-receptors from nin, noradrenaline, leukotriene and calcium in rat, rabbit guinea pig cerebellum membranes (Ki = 44 nM). This affin- or guinea pig specific isolated organs (caudal artery, tho- ity observed for bilastine was 5-fold greater than values for racic aorta and ileum or trachea, respectively). Similar fexofenadine and 3-fold greater than values for cetirizine effects were also reported for cetirizine and fexofenadine (Table 2). (17). These findings were supported by isolated organ studies in The greater selectivity of bilastine for H1-receptors is a guinea pig ileum and trachea smooth muscle. In guinea pig promising finding in these early studies as activity at other ileum, bilastine displayed competitive properties up to 33 nM receptors is often associated with a poor tolerability profile (36). These findings suggest that bilastine may be a more attractive treatment in allergic conditions compared to other, Table 2 Histamine H -receptor binding and antagonism of bilastine 1 less selective, antihistamines. compared with cetirizine and fexofenadine. Ki values were obtained In addition to effects mediated via H1-receptor blockade, from binding studies in guinea pig cerebellum whereas pA2 and second-generation antihistamines putatively produce a variety pD’2 values were obtained from antagonism studies in guinea pig of effects through modulation of anti-inflammatory activity. ileum (17). pA2 and pD’2 are mathematical parameters that define the in vitro ability of the antagonist to inhibit the agonist Reported down-regulatory activity of bilastine on inflammatory agents provides optimism that it could be effective in H1-antagonist Ki (nM) pA2 pD’2 allergic diseases via inhibition of histamine-producer cells (37). In vitro studies in human mast cells (HMC-1) and gran- Bilastine 44 8.0 6.2 ulocytes showed that bilastine inhibited both spontaneous Cetirizine 143 7.3 5.2 and activated histamine, interleukin-4 (IL-4) and tumour Fexofenadine 246 – 6.2 necrosis factor-a (TNFa) release (37).

Allergy 65 (Suppl. 93) (2010) 1–13 ª 2010 John Wiley & Sons A/S 3 Bilastine in allergic rhinoconjunctivitis and urticaria Bachert et al.

Table 3 Antihistaminic effects of bilastine in vivo compared to other H1-receptor antagonists (38)

Potency of bilastine

Administration of H1- compared to cetirizine Study Measurement Species/Strain receptor antagonists and fexofenadine

Histamine-induced Determination of Male Wistar rats Oral, 1 h prior to allergic ED50 (mg/kg) capillary permeability Evans Blue (EB) stimulus Bilastine: 2.5 in dorsal skin leakage in dorsal Cetirizine: 2.3 skin papules Fexofenadine: 10

Histamine-induced Determination of EB Male Wistar rats Intravenous, 5 min prior ED30 (lg/kg) capillary permeability leakage in dorsal to allergic stimulus Bilastine: 83 in dorsal skin skin papules Cetirizine: 281

Histamine-induced Determination of EB Male albino Intravenous, 5 min prior ED50 (lg/kg) microvascular leakage in trachea Dunkin-Hartley to allergic stimulus Bilastine 185 extravasation guinea pigs Cetirizine 168 Fexofenadine 773

Histamine-induced Measurement of Male albino Intravenous, prior to ED50 (lg/kg) bronchospasm bronchospasm Dunkin-Hartley allergic stimuli at 2, 10, Bilastine 4.6 guinea pigs 20, 30, 40, 50 and 60 min Cetirizine 53.3 post-treatment.

Lethality induced by Measurement of the Male albino Oral, 1 h prior to allergic ED50 (mg/kg) subcutaneous number of deaths Dunkin-Hartley stimulus Bilastine 0.2 injection of histamine over 24 h. guinea pigs Cetirizine 0.2 Fexofenadine 1.7

Lethality induced by Measurement of the Wistar rats Oral, 1 h prior to injection of ED50 (mg/kg) intravenous injection number of deaths Compound 48/80 Bilastine 2.3 of Compound 48/80 over 2 h. Cetirizine 1.2 Fexofenadine 6.8

Evidence from preclinical investigations highlights the Preclinical: in vivo studies specificity of bilastine for H1-receptors compared with other The inhibitory effects of bilastine on histamine release and histamine receptors and other receptor subtypes. In vivo activity at H1-receptors have translated into beneficial effects experimentation confirmed the antihistaminic and antiallergic in animal models of histamine-mediated inflammation activity which was comparable to that of the established sec-

(Table 3). For example, it decreased microvascular leakage ond-generation H1-antagonist cetirizine. from the trachea of guinea pigs and from the dorsal skin of rats, and reduced histamine-induced bronchospasm and hista- Preclinical: toxicology mine- and compound 48/80-induced lethality in guinea pigs (38). In general, bilastine exhibited similar efﬁcacy to cetiri- In vivo studies have investigated the toxicology of bilastine for zine in terms of antihistaminic activity, although there were periods of up to 2 years. For example in a 2-year oncogenicity differences in some in vivo assays. Of note, repeating hista- study, bilastine administered at a dosage of 2000 mg/kg per mine-mediated capillary permeability studies showed that day to mice and 5000, 15 000 and 30 000 ppm to rats resulted bilastine was more potent than cetirizine following intrave- in similar survival rates and causes of death as placebo in these nous administration and both drugs were more potent than rodent species (39). In this study, bilastine displayed no carcin- fexofenadine (38). ogenic potential in rats or mice. Bilastine was considered to In vivo investigations have also assessed the efﬁcacy of bi- display no carcinogenic potential as the type and incidence of lastine in reducing allergic responses to stimuli other than lesions diagnosed during the course of the study are commonly histamine (Table 4). Bilastine was effective in reducing per- diagnosed in animals of the strains and ages used (39). meability mediated via the passive cutaneous anaphylaxis (PCA) reaction in rats; the Schultz–Dale reaction in guinea Preclinical: pharmacokinetic studies pig ileum; IgG-dependent active cutaneous anaphylaxis (ACA) reaction or an IgE-dependent ACA reaction in mice; In vivo studies have investigated the pharmacokinetic proper- and passive Arthus reaction in mice induced by sheep red ties of bilastine in various species, primarily dogs and blood cells. Bilastine was at least as effective as cetirizine and rodents. Cmax and area under the curve (AUC) of bilastine more effective than fexofenadine in reducing these different increased proportionally to dose, up to a single oral dose allergic responses (Fig. 2) (17, 38). of 50 mg/kg (40). The values for these parameters were

4 Allergy 65 (Suppl. 93) (2010) 1–13 ª 2010 John Wiley & Sons A/S Bachert et al. Bilastine in allergic rhinoconjunctivitis and urticaria

Table 4 Antiallergic effects of bilastine in vivo compared to other H1-receptor antagonists (38)

Potency of bilastine Administration of compared to cetirizine

Study Measurement Species/Strain H1- receptor antagonists and fexofenadine

Passive cutaneous Determination of Evans Male Wistar rats Oral, 1 h prior to allergic ED50 (mg/kg) anaphylaxis (PCA) reaction Blue (EB) leakage in stimulus Bilastine 7.6 induced by homologous serum dorsal skin papules Cetirizine 2.2 Fexofenadine 62.6

PCA induced by Determination of Male Wistar rats Oral, 1 h prior to allergic ED50 (mg/kg) monoclonal antibodies EB leakage in stimulus Bilastine 6.0 dorsal skin papules Cetirizine 4.3 Fexofenadine 58.8

IgG-dependent active Determination of EB Male CD1 mice Oral, 1 h prior to allergic ED30 (mg/kg) cutaneous anaphylaxis leakage in mouse ear stimulus Bilastine 4.2 (ACA) reaction Cetirizine 1.1 Fexofenadine 8.9

IgE-dependent active Determination of EB Male CD1 mice Oral, 1 h prior to allergic ED30 (mg/kg) cutaneous anaphylaxis leakage in mouse ear stimulus Bilastine 3.8 (ACA) reaction Cetirizine 0.7 Fexofenadine 9.4 Type III allergic reaction: Measurement of paw Male CD1 mice Oral Bilastine: 28% inhibi- Passive Arthus reaction swelling tion at 50 mg/kg induced by sheep red No effect of cetirizine blood cells or fexofenadine. Type IV allergic reaction: Measurement of ear Male CD1 mice Oral, topical No effect of bilastine, contact dermatitis swelling cetirizine or fexofena- induced by oxazolone dine. generally 10-fold greater in dogs than in rats at equivalent over the period of the study, which was 26 weeks in rats and doses. Dose-dependent kinetics were also demonstrated in mice and 56 weeks in dogs (following oral or iv administra- mice, rats and dogs and in female rabbits, over a range of tion of doses up to 2000 mg/kg per day in rodents and oral doses up to a maximum of 2000 mg/kg per day in a 800 mg/kg per day in dogs) (41). long-term administration study (41). New antihistamines should be developed with minimal Bioavailability measurements have varied between species ability to enter the brain. This is dependent upon several fac- and gender. For example, while bilastine exhibited no differ- tors including p-glycoprotein-mediated transport. Studies in ences in plasma levels between the sexes in rats and dogs, rats assessed the p-glycoprotein sensitivity of bilastine at a there were significant differences between male and female dose of 20 mg/kg using the p-glycoprotein inhibitor, valspo- mice (41). In dogs, values of 42–69% were reported for bio- dar. Measurement of maximal plasma bilastine concentration availability with a clear trend of increasing bioavailability indicated that bilastine is a good substrate for p-glycoprotein with dosage (from 10 to 50 mg/kg). In contrast, bioavailabil- and thus will be prevented from entering the brain (42). This ity in rats was 25–61% with no observable increase with dose suggests that bilastine will have minimal impact on the cen- (40). The liver and lungs have virtually no intrinsic ability to tral nervous system (CNS). metabolise bilastine (42). An in vitro study confirmed this Preclinical assessment of the pharmacokinetic profile of bi- finding as no metabolism of [14C]-bilastine was reported in lastine indicates dose-dependent kinetics following oral rat, dog or human hepatocytes demonstrating its stability in administration. Bioavailability estimates are between 25% this in vitro system (43). and 69%, with considerable variation between species. The The tissue distribution of bilastine was assessed via quanti- fact that bilastine undergoes minimal hepatic clearance, and tative whole body radiography in male and female Sprague is eliminated in the faeces and urine as unchanged drug, sup- Dawley rats and male Lister Hooded rats following oral ports a reduced possibility of interactions with other drugs. administration of [14C]-labelled drug. Radioactivity was No accumulation was observed in the CNS, a promising find- widely distributed to tissues, with higher values found in the ing in terms of minimising possible sedative/psychomotor gastrointestinal tract, liver and kidneys, correlating with pat- effects. terns of elimination. There was no accumulation of radioactivity in the brain or other peripheral tissues (44). A long Clinical pharmacodynamic studies term study involving several species of laboratory animals including Wistar rats, Sprague–Dawley rats, rabbits, CD1 Given the promising in vitro and in vivo evidence regarding mice and beagle dogs reported no evidence of accumulation bilastine as an antihistaminic and antiallergic agent, early

Allergy 65 (Suppl. 93) (2010) 1–13 ª 2010 John Wiley & Sons A/S 5 Bilastine in allergic rhinoconjunctivitis and urticaria Bachert et al.

bilastine in healthy male volunteers (46). This was confirmed in simulated computer models using concentration-time data from 310 healthy volunteers. These programs indicated that bilastine fits a two-compartmental population model with first-order absorption and elimination (46). The apparent volume of distribution of the central compartment (Vc/F) was 59.2 l and the apparent volume of distribution of the peripheral compartment (Vp/F) was 30.2 l. Determination of pharmacokinetic parameters following single and 14 days once daily administration provided no evidence of accumulation (47). A Phase I mass balance study in healthy volunteers investigated absorption, metabolism and excretion following a single oral dose of [14C]-bilastine 20 mg. Radiolabelled bilastine was eliminated exclusively in the faeces (67%) and urine (33%). Measurement of metabolites in the plasma, urine and faeces indicated that bilastine is not metabolised in humans and is almost exclusively eliminated as unchanged drug (48). Bilastine metabolism was additionally defined using Caco-2 cells, with and without induction of the two main cyto- chromes involved in intestinal metabolism: CYP1A1 and CYP3A4. No metabolites were produced as a result of cellular activity, indicating an absence of intestinal metabolism Figure 2 Reduction in the histamine-induced increase in capillary (49). Additional in vitro studies in human microsomes and permeability (CP) in rats following (A) oral and (B) intravenous hepatocytes showed that bilastine is neither an inducer nor administration of bilastine or cetirizine (38). NS, not significant; an inhibitor of CYP450 isoenzymes (50). *P < 0.05, **P < 0.01, ***P < 0.001. Studies in healthy male and female volunteers reported no

clinically signiﬁcant gender-related differences in Cmax, AUC(0-t) and AUC(0-inf). In contrast, mean peak plasma con- pharmacological studies have aimed to assess these properties centrations were higher in younger subjects (18–35 years) in healthy volunteers (Table 5). than in those aged >65 years. In this study, highest values

When selecting an H1-antihistamine, patients are con- for Cmax were observed in young females, although total cerned with a rapid onset of action, good efficacy, a long exposure to bilastine (AUC(0-inf)) was very similar in all duration of action and freedom from unwanted effects. A groups studied (51). Simulated pharmacokinetic models have widely used model to determine these parameters is the also assessed parameters such as age, gender, body weight, wheal and flare reaction following histamine skin prick height, pulse rate, and albumin, bilirubin and creatinine testing. plasma concentrations, but none of these variables had a sig- A recent phase I study in healthy male volunteers evalu- nificant effect on the pharmacokinetic profile of bilastine ated the effect of five different bilastine single doses (2.5, 5, (46). 10, 20 and 50 mg) on histamine-induced wheal and flare over Due to the frequent and often long-term administration of a 24 h period, compared with a single 10 mg oral dose of antihistamines, clinical assessment of drug interactions is nec- cetirizine (45). The results of this investigation indicated that essary in the development of newer agents. Studies in healthy bilastine was at least as effective as cetirizine in reducing his- volunteers assessed the potential interaction between bilastine tamine-mediated effects in healthy volunteers. Importantly, and the known p-glycoprotein and cytochrome P450 3A4 20 and 50 mg of bilastine reduced the wheal and flare inhibitors ketoconazole (52), erythromycin and diltiazem response significantly more rapidly than cetirizine, an estab- (50). Co-administration of bilastine with either erythromycin lished second-generation H1-antihistamine (Fig. 3). or ketoconazole resulted in a significant increase in the AUC and Cmax values for bilastine, whilst the duration of exposure remained unchanged. The pharmacokinetic parameters of Clinical pharmacokinetic studies erythromycin and ketoconazole were unaltered in the pres-

The clinical pharmacokinetic properties of bilastine are sum- ence of bilastine. Increases in the Cmax and AUC of bilastine marised in Table 6. Studies in human volunteers demon- were also observed when co-administered with diltiazem, strated that bilastine is rapidly absorbed after oral although at a lower level compared with erythromycin or treatment, reaching maximal plasma concentrations 1–1.5 h ketoconazole. These changes in the pharmacokinetic parame- after administration of both single and multiple doses (46, ters of bilastine are almost certainly due to the inhibition of 47). Assessment of pharmacokinetic parameters including p-glycoproteins by ketoconazole, erythromycin and diltiazem,

AUC(0-t) and Cmax have indicated a linear proﬁle within the resulting in an alteration in intestinal transport systems and 10–220 mg dose range for both single and multiple doses of increased absorption.

6 Allergy 65 (Suppl. 93) (2010) 1–13 ª 2010 John Wiley & Sons A/S Allergy al. et Bachert 65

Spl 3 21)1–13 (2010) 93) (Suppl. Table 5 Studies comparing the efﬁcacy and safety of bilastine in reducing allergic symptoms

Number and type of Aim Type of trial Dosing regimen subjects Main ﬁndings Safety

Allergic rhinitis studies To assess the effects of Phase II study. Randomised, 20 mg bilastine, 10 mg 75 Seasonal allergic Bilastine reduced allergic Well tolerated, similar

ª bilastine on allergic symptoms double-blind, cetirizine, 120 mg rhinoconjunctivitis symptoms with a rapid onset safety profile to 00Jh ie osA/S Sons & Wiley John 2010 in patients exposed to placebo-controlled, single fexofenadine or (SAR) patients and a long duration of action. placebo. aeroallergen in the Vienna oral dose, crossover study. placebo. (symptom-free prior Bilastine was similar in activity Challenge Chamber (VCC) to study period). to cetirizine and maintained compared with cetirizine and the effect for longer than fexofenadine. (55). fexofenadine. To compare the efficacy of Phase III study. 20 mg bilastine, 10 mg 683 SAR patients Bilastine reduced symptoms of Similar safety profile to bilastine with cetirizine and Randomised, double-blind, cetirizine or placebo, SAR more effectively than placebo. Better placebo in the symptomatic placebo-controlled study. once daily for 14 days. placebo. Bilastine and cetirizine tolerated than treatment of SAR. (15). were equally effective. cetirizine. To compare the safety and Phase III study. 20 mg bilastine, 5 mg 721 SAR patients Bilastine reduced symptoms of Well tolerated, similar efficacy of bilastine to Randomised, double-blind, desloratadine or SAR more effectively than safety profile to desloratadine in SAR patients placebo-controlled study. placebo. Once daily placebo. Bilastine and placebo. (11). for 14 days. desloratadine were equally effective. Bilastine reduced total symptom score (TSS) and improved quality of life (QoL) compared with

placebo. urticaria and rhinoconjunctivitis allergic in Bilastine To compare the efﬁcacy of Phase III study. Randomised, 20 mg bilastine, 10 mg 651 PAR patients Bilastine and cetirizine produced Well tolerated; see bilastine to cetirizine in double-blind, placebo cetirizine or placebo comparable effects in reducing ‘Safety studies’ perennial allergic and active-controlled study. once daily for 28 days TSS from baseline. However these section. rhinoconjunctivitis (PAR) effects were not different from patients (50). placebo. To assess the long term Open label extension study. 20 mg bilastine once 513 PAR patients Bilastine signiﬁcantly reduced Well tolerated; see effects of bilastine over a daily nasal symptom scores (NSS) and ‘Safety studies’ 12 month period (50). non-NSS, as well as individual section symptom scores (sneezing, runny nose, nasal itching, nasal congestion, tearing and ocular redness) compared with baseline values. 7 8 Table 5 (Continued) urticaria and rhinoconjunctivitis allergic in Bilastine

Number and type of Aim Type of trial Dosing regimen subjects Main ﬁndings Safety

Urticaria studies To assess the effect of Phase I study. Randomised, 2.5, 5, 10, 20 and 50 mg 21 healthy male 20 mg bilastine inhibited Well tolerated, similar bilastine on histamine-induced double-blind, bilastine, 10 mg volunteers histamine-induced wheal and safety profile to wheal and flare, compared to placebo-controlled, single cetirizine or placebo flare at levels comparable to placebo. cetirizine (58) oral dose, crossover study cetirizine. To assess the efficacy of Phase II study. Randomised, 10, 20, 30 mg bilastine 152 chronic urticaria All doses of bilastine were Well tolerated, similar bilastine administered at double-blind, or placebo. patients superior to placebo in terms safety profile to different doses in patients placebo-controlled study. of reducing TSS. placebo. with chronic idiopathic urticaria (55). To assess the clinical efficacy Phase III study. 20 mg bilastine, 516 chronic urticaria Bilastine reduced TSS compared Well tolerated, similar and safety of bilastine in Randomised, double-blind, levocetirizine 5 mg or patients to placebo. Bilastine and safety profile to patients with chronic idiopathic placebo-controlled study. placebo. Once daily for levocetirizine were equally placebo. urticaria. (32). 28 days. effective.

Safety studies To assess the CNS effects Pharmacodynamic 20, 80 mg bilastine, 25 mg 24 healthy volunteers Bilastine did not affect Well tolerated, similar of the possible interaction interaction study. hydroxyzine, 10 mg cetirizine psychomotor scores when safety proﬁle to between bilastine and alcohol, Randomised, or placebo. administered with alcohol. placebo. compared to hydroxyzine and double-blind, placebo and Alcohol: 0.8 g/kg Cetirizine and hydroxyzine both placebo (58). positive-controlled, crossover signiﬁcantly enhanced the study. effects of alcohol.

Allergy To assess the effect of Thorough QT/QTc study. 20, 100 mg bilastine, 30 healthy volunteers Bilastine did not produce any Well tolerated, similar therapeutic and Randomised, double-blind, 20 mg bilastine + 400 mg significant effects on QTc safety profile to supratherapeutic doses of placebo- and ketoconazole, 400 mg interval at either dosage. Small placebo. 65 bilastine on the QTc interval positive-controlled moxifloxacin or changes occurring when Spl 3 21)1–13 (2010) 93) (Suppl. (59). crossover study placebo. bilastine was co-administered with ketoconazole were due to the antifungal agent. To assess the long term Open label extension 20 mg bilastine 513 PAR patients Bilastine was well safety of bilastine over a safety study. tolerated, with only 18 12 month period (50). subjects (3.5%)

ª withdrawing from the 00Jh ie osA/S Sons & Wiley John 2010 study due to AEs. These AEs were not considered to be due to study medication. ahr tal. et Bachert To determine the peripheral Phase I study. 20, 40, 80 mg bilastine, 21 healthy Psychomotor impairment Well tolerated, and central effects of single Randomised, double-blind, 25 mg hydroxyzine or volunteers was not observed with the 20 similar safety and repeated doses of placebo-controlled study. placebo. and 40 mg doses of bilastine. proﬁle to placebo. bilastine (57) 80 mg: minor CNS effects. Bachert et al. Bilastine in allergic rhinoconjunctivitis and urticaria

100 Two single dose (20 mg) studies in healthy volunteers investigated the effect of food intake on the bioavailability of

80 bilastine. Bioavailability was reduced by 30% when bilastine was taken with high fat food, and by 25% with standard low fat food, compared with values obtained under fasting condi- 60 Placebo tions (50). This observation should be taken into account 2.5 mg when considering the administration of bilastine. 40 5 mg 10 mg 20 mg Clinical properties 20 50 mg Cetirizine Clinical efﬁcacy in rhinoconjunctivitis 0 Preliminary clinical studies with bilastine in allergic rhinocon-

% inhibition basal wheal surface junctivitis patients have yielded promising results (Table 5). –20 Seventy-ﬁve asymptomatic volunteers with SAR were chal- lenged with grass pollen in the Vienna Challenge Chamber.

–40 This is an experimental setting in which subjects are exposed 04812162024 to specific allergens for prolonged periods, under controlled Time (h) and reproducible conditions. In this study, subjects were chal- lenged with grass pollen for 6 h on two consecutive days. A Figure 3 Percentage inhibition of histamine-induced wheal surface single oral dose of bilastine 20 mg taken 2 h after the start of area over time in subjects treated with bilastine (2.5, 5, 10, 20 and the allergic provocation effectively reduced nasal symptom 50 mg), cetirizine 10 mg or placebo (45). scores (NSS), global symptom scores, nasal secretions and eye symptoms compared to placebo on day 1 (54). Similar Table 6 Overview of the pharmacokinetic properties of bilastine results were obtained with cetirizine 10 mg. Although the 20 mg based upon data from single- and multiple dose studies effects of bilastine and fexofenadine 120 mg were similar dur- applied to a two-compartmental model with first-order absorption ing the first 4 h after administration, bilastine was signifi- and elimination (47) cantly more effective than fexofenadine between 22 and 26 h after drug intake. Furthermore, bilastine was shown to have Parameters Pharmacokinetic values a rapid onset of action (1 h) and a long duration of action

Cmax (ng/ml) 220 (>26 h). Like cetirizine and fexofenadine, bilastine was safe

Tmax (h) 1.3 and well tolerated in this short term study.

AUC0-t (h*ng/ml) 1105 Bilastine 20 mg also effectively improved total symptom

Ka (per hour) 1.5 score (TSS), compared with placebo over a 14 day period in

Ke (per hour) 0.3 two randomised, double-blind, placebo controlled, studies

Vc/F (l) 59.2 performed in allergic rhinoconjunctivitis patients (n = 721, Vp/F (l) 30.2 n = 683) (11, 15). Total symptom score incorporated NSS Plasma binding (%) 85 (sneezing, rhinorrhoea, nasal itching, and nasal congestion) Q/F (l/h) 1.6 and non-NSS (ocular tearing and redness, itching of the ears/ CL/F (l/h) 18.1 palate). Two other second-generation antagonists, cetirizine Distribution t1/2a (h) 2.1 (15) and desloratadine (11), were also assessed in these stud- Elimination t1/2b (h) 14.5 ies and bilastine proved to be as efficacious as these drugs (Fig. 4). Bilastine had a better tolerability profile than cetiri- Cmax, maximum plasma concentration; Tmax, time taken to reach zine in terms of CNS effects, particularly with regards to a Cmax; AUC, area under the curve; Ka, absorption rate constant; Ke, lower incidence of somnolence. Additional parameters mea- elimination rate constant; Vc, volume of distribution in central com- sured to assess the efficacy of bilastine included patient-evalu- partment; Vp, volume of distribution in peripheral compartment; Q, clearance between the compartments; CL, clearance; F, bioavail- ated discomfort associated with rhinoconjunctivitis and QoL. ability. Bilastine improved both of these endpoints compared with placebo (P < 0.001), and the findings were comparable to Co-administration with grapefruit juice reduced plasma those produced by desloratadine (11) and cetirizine (15).

Cmax, AUC(0-t), and AUC(0-inf) values for bilastine by 33%, In a 28 day multicentre study involving 651 patients with 24% and 24% respectively, compared to bilastine alone, in a perennial allergic rhinoconjunctivitis, bilastine 20 mg and ce- randomised two-way crossover study in healthy adults. These tirizine 10 mg both reduced TSS compared to baseline. How- data demonstrate that grapefruit juice reduces the systemic ever, these effects were not signiﬁcantly different to placebo exposure of bilastine (53). This is most probably due to the (Table 5). Post hoc analysis showed this was indicative of a effects of grapefruit ﬂavonoids on intestinal transporter sys- considerable placebo effect in one region of the study. tems such as p-glycoproteins and organic anion transporting Following the short-term double-blind trial, subjects peptide. (n = 513) received bilastine 20 mg once daily for 12 months

Allergy 65 (Suppl. 93) (2010) 1–13 ª 2010 John Wiley & Sons A/S 9 Bilastine in allergic rhinoconjunctivitis and urticaria Bachert et al.

Figure 4 Effect of treatment with bilastine 20 mg, desloratadine 5 mg, or placebo, on mean total symptom score, recorded as reﬂective 12 hourly scores in the morning (m) and evening (e) over a period of 14 days (11).

in an open-label extension study. Whilst safety was the pri- plasma concentrations over time for bilastine after four con- mary endpoint (see Tolerability and safety section; Table 5), secutive oral doses of 5, 10 and 20 mg of the drug were per- over the course of the 12 months’ follow-up bilastine signifi- formed in order to determine the optimal dosage relative to cantly reduced NSS and non-NSS, as well as individual the therapeutic endpoint of wheal/flare inhibition described symptom scores (sneezing, runny nose, nasal itching, nasal for adults. This study concluded that four consecutive doses congestion, tearing and ocular redness) compared with base- of 10 mg/day in children (aged 2, 6 and 12 years) maintained line values (50). bilastine concentrations above the IC50 value required for These results indicate that bilastine 20 mg once daily was wheal inhibition. Therefore, in this simulated setting, bilastine significantly superior to placebo and comparable to cetirizine 10 mg was considered effective in children aged 2–12 years. 10 mg and desloratadine in relieving symptoms of SAR, and In infants, a dose of 5 mg/day was calculated to maintain furthermore, it demonstrated a significantly better adverse antihistaminic activity throughout the treatment period (56). event profile than cetirizine. Despite a significant placebo Clinical studies to confirm the efficacy and safety of these effect, bilastine 20 mg decreased nasal and non-nasal symp- doses in children are on-going. toms for up to 12 months and was well tolerated in a group of PAR patients. Tolerability and safety Assessment of the safety of bilastine indicates that it is a well Clinical efficacy in urticaria tolerated antihistamine and doses of 20–100 mg were no dif- Bilastine doses of 10, 20 and 30 mg were all superior to pla- ferent in terms of Adverse Events (AEs) profile from placebo cebo in terms of reducing TSS (P = 0.003), based on the in studies involving healthy volunteers who received the drug variables of itching and number and diameter of wheals in for up to 14 days (47). Similar tolerability was also reported 218 chronic urticaria patients (55). The efficacy of bilastine for bilastine and placebo in clinical trials in patients with (20 mg) was also compared with levocetirizine 5 mg in a allergic rhinoconjunctivitis (11, 15). Furthermore, bilastine recent double-blind, placebo-controlled, randomised, parallel (20 mg) had an improved safety profile, with reduced inci- group phase III study in 516 chronic urticaria patients (32). dences of fatigue and somnolence, compared with cetirizine Bilastine and levocetirizine were equally effective, significantly (10 mg) over a 14 day period (15). A recent 28-day double- reducing TSS and sleep disturbances, and improving QoL blind study was followed by a 12 month open-label safety and urticaria-associated discomfort compared with placebo extension and involved a total of 513 patients treated with bi- (P < 0.001), from day 2 to the end of the 28-day treatment lastine 20 mg daily. Of this population, 18 subjects (3.5%) period. withdrew due to AEs. However, these AEs were not consid- As estimates suggest that up to 40% of children in some ered by the investigator to be due to study medication (50). developed countries suffer from allergies (11) it is necessary Based upon these early findings bilastine appears to very well to establish a dose of bilastine for the paediatric population. tolerated at usual dosages and may prove to be an attractive

A simulated model of pharmacokinetic parameters based on alternative compared to some of the more established H1- data from adults was recently developed (56). Simulations of receptor antagonists (15).

10 Allergy 65 (Suppl. 93) (2010) 1–13 ª 2010 John Wiley & Sons A/S Bachert et al. Bilastine in allergic rhinoconjunctivitis and urticaria

diac action potential and are not related to H -receptor Lack of CNS effects 1 antagonism, i.e. it is not a class effect (2). However, given the Criteria for determining whether a new antihistamine may be seriousness of the effects, the development of any new anti- classified as non-sedating have been proposed by the Consen- histamine now involves vigorous testing of cardiotoxicity, sus group On New Generation Antihistamines (CONGA) (2). including assessment of the QTc interval. These factors are (i) incidence of subjective sleepiness, (ii) Bilastine, fexofenadine, desloratadine and cetirizine dose- objective cognitive and psychomotor functions and (iii) posi- dependently blocked human ether-a-go-go-related gene tron emission tomography (PET) measurement of H1-recep- (HERG) current in HEK-293 cells transfected through the tor occupancy. Balancing the beneficial peripheral H1 lipofectamine method with the HERG clone. IC50 values inhibitory effects with unwanted CNS effects involves deter- of 6.5, 12.5, 1.4 and 1.1 lM, respectively were calculated. mining at what dose the drug is clinically effective, whilst Bilastine was 5-fold less potent than cetirizine in this model minimising adverse effects. A clinical study was performed to (50). characterise the CNS response to three doses of bilastine (20, Recently the effect of therapeutic (20 mg) and suprathera- 40 and 80 mg) compared with that of placebo and hydroxy- peutic (100 mg) doses of bilastine on QTc interval was zine 25 mg (a sedating antihistamine included as positive con- assessed in accordance with FDA and ICH guidelines (ICH trol) in healthy young volunteers (57). The greatest motor E14). This was a multiple-dose, randomised, double-blind, impairment was documented for hydroxyzine 25 mg. As crossover trial with placebo and active control (moxifloxacin motor impairment was not observed with the 20 and 40 mg 400 mg). Bilastine did not produce any significant effects on doses of bilastine, these results provide optimism for bilastine QTc interval at either dosage. Furthermore, changes that as a potential treatment in allergic conditions. The data also occurred when co-administered with ketoconazole 400 mg suggest that there is dissociation between the peripheral and were relatively small and likely to be due to the antifungal central antihistamine effects of bilastine. Subjective reports agent (59). on mood indicated that the greatest negative impact was with hydroxyzine 25 mg, while bilastine 20 mg was no different Place in therapy from placebo. A number of studies have assessed the CNS effects of bi- Current antihistamines have –in most clinical circumstances- lastine in combination with others drugs known to cause a good level of efficacy and therefore development of new sedation. For example, in a double-blind, crossover study, bi- antihistamines is primarily concerned with improving their lastine 20 mg once daily for 8 days did not increase the seda- tolerability and decreasing the incidence of AEs, increasing tive effects of lorazepam 3 mg (as assessed by objective their potency, extending their duration of action and/or pro- psychomotor testing) in healthy volunteers (50). In a similarly ducing agents which act more quickly. In vitro studies have designed study, bilastine 20 mg did not affect psychomotor confirmed the specificity of bilastine for H1-receptors, and scores when administered with alcohol. This is an encourag- both preclinical and clinical investigations have shown that ing finding since other antihistamines evaluated in this study bilastine has similar efficacy to cetirizine, desloratadine and (cetirizine 10 mg and hydroxyzine 25 mg) both significantly levocetirizine in terms of reducing allergic symptoms. Clini- enhanced the effects of alcohol (58). A phase I study in cal findings indicate that bilastine has a rapid onset of healthy volunteers investigated the effects of repeated doses action and a 20 mg single dose is effective throughout a 24- of bilastine (20 and 40 mg) on driving ability compared with h period. Furthermore, bilastine has been associated with hydroxyzine 50 mg and placebo. Bilastine had no effect on improved QoL in allergic rhinoconjunctivitis and urticaria the primary efficacy variable, Standard Deviation of Lateral patients. Position (SDLP) in the Road Tracking Test. However, SDLP In terms of safety and tolerability, early evidence indicates was significantly altered by hydroxyzine 50 mg, in compari- that bilastine 20 mg is very well tolerated with minimal son to placebo in this setting (50). In terms of the incidence adverse effects. Indeed, in clinical trials it was no different of subjective sleepiness and objective cognitive and psycho- from placebo in terms of tolerability and this makes this motor performance, bilastine 20 mg demonstrates a promis- novel antihistamine a potentially exciting treatment for aller- ing profile as a non-sedative H1-receptor antagonist. gic diseases. The removal of astemizole and terfenadine from However, given the CONGA recommendations, PET mea- the marketplace has raised the awareness and some concerns surement of H1-receptor occupancy is recommended to fully regarding antihistamines and cardiotoxicity (60). In this explore this potential. regard bilastine underwent a well-controlled QTc assessment according to FDA/ICH guidelines, and even at supratherapeutic dosages it was not associated with adverse effects on Cardiac safety the QTc interval and this highlights its cardiovascular safety. The second-generation antihistamines astemizole and terfena- In addition, bilastine appears to have minimal potential for dine have been associated with severe adverse cardiac effects drug-drug interactions given that it is not metabolised in the including QT interval prolongation and torsades de pointes liver and does not affect CYP450 isoenzymes. ventricular tachyarrhythmias and were withdrawn from the Thus, based on its pharmacological properties and early market. Such effects are attributed to direct blockade of clinical trials experience it appears that bilastine has a potassium channels controlling the repolarisation of the car- similar efficacy to other second-generation H1-receptor

Allergy 65 (Suppl. 93) (2010) 1–13 ª 2010 John Wiley & Sons A/S 11 Bilastine in allergic rhinoconjunctivitis and urticaria Bachert et al. antagonists, but may possess a more favourable safety place in the treatment of diseases for which an antihista- proﬁle. Larger, long term trials are required to fully eluci- mine is advocated such as allergic rhinoconjunctivitis and date this potential and to help determine its overall urticaria.

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