Bilastine

Chemistry

Bilastine, or 2-[4-[2-[4-[1-(2-ethoxyethyl) benzimidazol-2-yl] piperidin-1-yl] ethyl] phenyl]-2-methylpropionic acid, is a novel molecule with a molecular weight of 463.6 daltons and a chemical structure similar to piperidinyl-benzimidazole. Bilastine can be therefore classified into the same chemical group as many of the new antihistamines on the market, although it is not structurally derived, nor is it a metabolite or enantiomer of any of them, but an original molecule designed with the intent of fulfiling all the requirements of a second-generation antihistamine.

Dosage

A therapeutic dosage of bilastine is 20 mg once a day orally and shows a rapid onset of action (within 30–60 minutes). It should be taken only by children older than 12 years and adults.

Pharmacodynamics

Bilastine binds to guinea-pig cerebellar histamine H1-receptors (Ki=44 nM) and to human recombinant histamine H1-receptors (Ki=64 nM) with an affinity comparable to that of astemizole and diphenhydramine, and superior than that of cetirizine by three-fold and fexofenadine by five-fold (Corcóstegui). In different murine models, bilastine by oral route, antagonizes the effects of histamine in a dose-dependent manner, with potency similar to that of cetirizine and between 5.5 and 10 times greater than that of fexofenadine.

Preclinical investigations demonstrate the affinity and specificity of bilastine for histamine H1-receptors compared with other histamine receptors subtypes and other 30 receptors from different amines. In vivo experimentation confirmed the antihistaminic and antiallergic activity, which was at least comparable to that of other second-generation H1-antihistamines such as cetirizine.

Clinical studies using different dosages were done on histamine-induced wheal and flare reaction over a 24-h period, compared with a single 10-mg oral dose of cetirizine. The results of this research indicated that bilastine was at least as efficient as cetirizine in reducing histamine-mediated effects in healthy volunteers. Remarkably, 20 and 50 mg of bilastine reduced the wheal and flare reaction significantly more quickly than cetirizine.

Clinical Efficacy

The clinical efficacy of bilastine in allergic rhinitis (AR) and urticaria has been assessed in 10 clinical assays in which over 4,600 patients were involved. All of them compared bilastine with placebo and another second generation antihistamine with confirmed efficacy (active comparator). In a first study performed under controlled conditions of allergen exposure and time of exposure with sensitised volunteers (Vienna Challenge Chamber), bilastine 20 mg shows an efficacy similar to that of cetirizine 10 mg for the relief of symptomatic seasonal AR (SAR), with a rapid onset of action (1 h) and a duration of action of at least 24 h. The duration of the effect of both compounds is higher than that of fexofenadine at a dose of 120 mg.

The studies on SAR were double-blind, placebo-controlled, parallel-group involving male and female patients over 12 year of age with symptomatic disease at the beginning of the study. Nasal symptoms (sneezing, rhinorrhea, nasal itching and congestion) were assessed both before treatment and during treatment period on a daily basis. Non nasal symptoms (itchy eye, watery eye, itchy ear and palate) were also assessed according to a 0–3 scale, so that the Total Symptoms Score (TSS) and other related parameters could clearly reflect daily evolution of SAR in each patient and treatment group. Parameters such as quality of life and discomfort were also assessed, and in the same way the type and frequency of AE, tolerability and general safety of treatment were registered. In this SAR studies the daily oral administration during 14 days of bilastine 20 mg proves to have the same efficacy than the administration of cetirizine 10 mg or than the administration of desloratadine 5 mg. Likewise, bilastine 20 mg shows a safety and tolerability profile similar to placebo and significantly superior to that registered for cetirizine, the risk of somnolence and fatigue being respectively 4 and 20 times lower at 1.8% and 0.4%.

The studies in urticaria were double-blind, placebo-controlled, parallel-group involving male and female patients over 18 year of age with symptomatic disease (idiopathic chronic urticaria) at the beginning of the study. Itching intensity as well as number and maximum size of wheals were assessed according to a 0–3 scale so that the Total Symptom Score (TSS) and other related parameters could clearly reflect the daily evolution of urticaria in each patient and treatment group. Parameters such as quality of life and discomfort were also assessed, and in the same way the type and frequency of AE, tolerability and general safety of treatment were registered. In this urticaria studies the daily oral administration during 28 days of bilastine 20 mg proves to have the same efficacy – for the reduction of TSS and the quality of life parameters- than the administration of levocetirizine 5 mg. Likewise, Bilastine 20 mg shows a safety and tolerability profile similar to placebo.

Recently, twenty patients with cold contact urticaria (CCU) were included in a randomized, crossover, double-blind, placebo-controlled 12-week study. They received placebo, 20, 40 or 80 mg of bilastine daily each for 7 days with 14-day washout periods. The primary variable was change in critical temperature thresholds (CTT). Secondary variables were changes in pruritus, levels of histamine, IL-6, IL-8 and TNF-α collected by skin microdialysis and safety and tolerability of bilastine. At doses of 20 mg was highly effective (P < 0.0001) in reducing CTT. Up-dosing to 80 mg significantly (P < 0.04) increased its effectiveness. At this dose, 19 of 20 (95%) patients responded to treatment, with 12 of 20 (60%) becoming symptom free. Only one patient was refractory to treatment. Microdialysis levels of histamine, IL-6 and IL-8 assessed 1-3 h after cold challenge (4 °C) were significantly (P < 0.05) decreased following up-dosing with 80 mg bilastine. Bilastine was effective in reducing the symptoms of patients with CCU. Increased efficacy of bilastine with fourfold up-dosing was without sedation and supports urticaria treatment guidelines.

Distribution

Bilastine distribution has an apparent volume of distribution of 1.29 L/kg, and has an elimination half-life of 14.5 h and plasma protein binding of 84–90%.

Absorption and bioavailability

Bilastine is most quickly absorbed with the absence of food, and reaches a mean peak plasma concentration of 220 ng/mL approximately 1 h after both single and multiple dosing. Absorption is reduced by a high-fat breakfast or fruit juice, and the estimated global oral bioavailability is approximately 60%. Bilastine has linear pharmacokinetics in the 2.5–220 mg dose range in healthy adult subjects without evidence of accumulation after 14 days of treatment.

Metabolism

Bilastine is not significantly metabolized in humans and is largely eliminated unchanged both in urine and feces – a third and two thirds of the administered dose, respectively, according to a Phase I mass-balance study with radiolabeled bilastine. Bilastine does not readily cross the blood brain barrier and is not metabolized by the liver. Ninety six percent of the administered dose is eliminated within 24 hours.

In relation to its antihistamine effect, oral doses of 20 mg daily of bilastine, measured as skin wheal-and-flare surface areas for 24 h, bilastine is capable of inhibiting 50% of the surface areas – throughout the whole administration interval.

Drug interactions and food effects

Preclinical data suggest the possibility of interactions between bilastine and drugs or food that are inhibitors or inducers of the P-glycoproteins. Coadministration of bilastine and grapefruit juice (a known P-glycoprotein-mediated drug transport activator) significantly reduced bilastine systemic exposure. This interaction is due to the known effect of grapefruit flavonoids on intestinal transporter systems such as P-glycoproteins and organic anion transporting peptide (OATP).

Safety and tolerability

Toxicity of bilastine investigated in preclinical toxicology studies in mice, rats and dogs after oral and intravenous administration showed no mortality observed after oral administration of massive doses. After intravenous administration, LD50 (lethal dose for 50% of animals) values were 33 and 45–75 mg/kg in mice and rats, respectively. No signs of toxicity were observed in any organ after bilastine massive overdosing, either orally (in mice, rats and dogs), or intravenously (in rats and dogs) during 4 weeks. No effects on fertility, no teratogenic or mutagenic effects, and no apparent carcinogenic potential were seen in the studies carried out in rats, mice and rabbits.

In clinical research, bilastine has proven to be well tolerated, with an adverse events profile similar to that of placebo in healthy volunteers, patients with AR and with chronic idiopathic urticaria. Although the tolerance profile of bilastine and levocetirizine or desloratadine were very similar, bilastine was markedly better tolerated than cetirizine in a clinical assay in SAR, with fewer adverse events in the bilastine group. No anticholinergic adverse events were observed in the clinical trials with bilastine. No serious adverse events were reported during the research and there were no clinically significant changes in vital signs, electrocardiography (ECG) or laboratory tests. Pharmacokinetic/pharmacodynamic profiles and studies in special populations indicate that bilastine as dose adjustment is not necessary in elderly patients, or in hepatic or renal insufficiency.

Recently a total of 12 healthy volunteers (males, 18 – 55 years) were included in a randomised, double-blind, cross-over clinical trial to assess occupation of brain histamine H1 receptors after administration of single doses of bilastine 20 mg, evaluated by positron emission tomography (PET) with [11C]-doxepin as radiolabeled drug. Hydroxyzine 25 mg (single dose) was used as positive control. For each subjects five brain regions-of-interest (ROI) were defined. This ROI were located on the cortical areas (frontal cortex, parietal cortex, occipital cortex, temporal cortex and insula) based on the known location of H1 receptors in the brain. The cerebellum was used as reference region to obtain the “binding potential” (BP) at baseline and after drug administration. Finally, H1 receptors occupancy (RO) as percentage was estimated as:

RO =100 • [BP placebo - BP antihistamine]/BP placebo,

where “BP placebo” corresponds to the binding potential measured after administration of placebo and “BP antihistamine” corresponds to the binding potential measured after administration of the antihistamine (bilastine or hydroxyzine). The secondary objectives were to determine blood concentrations of bilastine at the time of PET. For each ROI, the BP parameter was calculated. The BP TOTAL was the mean value of 5 ROI studied. Results showed less BP mean values in all different brain ROI and in BP TOTAL with hydroxyzine 25 mg than with bilastine 20 mg, and also less BP with hydroxyzine than with placebo in all different ROI. These differences were statistically significant. BP TOTAL was 0.2561 ± 0.0809 for placebo, 0.2601 ± 0.0723 for bilastine 20 mg and 0.1299 ± 0.0671 for hydroxyzine 25 mg. For each ROI, the RO parameter was calculated according to formula before indicated. Lower RO in all ROI and in RO TOTAL was observed with bilastine 20 mg in comparison to hydroxyzine 25 mg. These differences were statistically significant (p<0.01). RO (%) TOTAL was -3.92 ± 14.39% for bilastine 20 mg and 53.95 ± 14.13% for hydroxyzine 25 mg. For both antihistamines the TEMPORAL was the cortex region with higher RO values. There was no significant linear relationship between individual values of the AUC0-2.5h of bilastine plasma concentration and the mean BP TOTAL. A correlation coefficient (r2) of 0.0634 (p>0.05, no significant) were calculated.

Cardiac safety

The clinical cardiac safety of bilastine has been assessed in all of the clinical trials performed so far (more than 3,500 patients treated with bilastine) and in a phase I study (Thorough QT/QTc study) designed according to the ICH E14 guidance and the most demanding requirements from the Food and Drug Administration (FDA). When electrocardiograms (ECG) data from all of the phase I studies are analysed, no significant alteration is appreciated in any of the parameters after administering bilastine at single doses (up to 11 times the therapeutic dose), nor at multiple doses (up to 10 times the therapeutic dose). Phase II and III studies on AR and urticaria (including the open-label extension phase of 12 months) do not reveal alterations in the ECG, nor significant prolongations of the QTc interval after administration of bilastine 20 mg.

The Thorough QT/QTc study was designed to assess the effect on the QT/QTc interval, both of the therapeutic dose (20 mg) and 100 mg of bilastine, but also the coadministration of the therapeutic dose with usual doses of ketoconazol (400 mg/day), a metabolism inhibitor and a P-gP dependent transport system. It was verified that bilastine 20 and 100 mg administered during 4 days, does not induce significant changes in the QT/QTc interval duration in any of the individuals. Likewise, coadministration of bilastine 20 mg and ketoconazol 400 mg does not produce any significant prolongation of the QT/QTc interval attributable to bilastine.

Side effects

Possible side effects include headache and drowsiness.

Uncommon side effects (affects 1 to 10 users in 1,000) include abnormal ECG heart tracing, blood tests which show changes in the way the liver is working, dizziness, stomach pain, tiredness, increased appetite, irregular heartbeat, increased weight, nausea (the feeling of being sick), anxiety, dry or uncomfortable nose, belly pain, diarrhea, gastritis (inflammation of the stomach wall), vertigo (a feeling of dizziness or spinning), feeling of weakness, thirst, dyspnoea (difficulty in breathing ), dry mouth, indigestion, itching, cold sores (oral herpes), fever, tinnitus (ringing in the ears), difficulty in sleeping, blood tests which show changes in the way kidney is working, and increased blood fats.