Bilastine vs. hydroxyzine: occupation of brain histamine H₁‐receptors evaluated by positron emission tomography in healthy volunteers

Abstract

AimA close correlation exists between positron emission tomography (PET)-determined histamine H1-receptor occupancy (H1RO) and the incidence of sedation. Antihistamines with H1RO <20% are classified as non-sedating. The objective was to compare the H1RO of bilastine, a second generation antihistamine, with that of hydroxyzine.MethodsThis randomized, double-blind, crossover study used PET imaging with [11C]-doxepin to evaluate H1RO in 12 healthy males (mean age 26.2 years), after single oral administration of bilastine (20 mg), hydroxyzine (25 mg) or placebo. Binding potentials and H1ROs were calculated in five cerebral cortex regions of interest: frontal, occipital, parietal, temporal, insula. Plasma bilastine concentrations, subjective sedation (visual analogue scale), objective psychomotor performance (digital symbol substitution test), physiological variables and safety (adverse events, AEs), were also evaluated.ResultsThe mean binding potential of all five regions of interest (total binding potential) was significantly greater with bilastine than hydroxyzine (mean value 0.26 vs. 0.13, P < 0.01; mean difference and 95% CI −0.130 [−0.155, 0.105]). There was no significant difference between bilastine and placebo. Overall H1RO by bilastine was significantly lower than that by hydroxyzine (mean value −3.92% vs. 53.95%, P < 0.01; mean difference and 95% CI 57.870% [42.664%, 73.075%]). There was no significant linear relationship between individual bilastine plasma concentrations and total binding potential values. No significant between-treatment differences were observed for sedation and psychomotor performance. Twenty-six non-serious AEs were reported. Sleepiness or sedation was not reported with bilastine but appeared in some subjects with hydroxyzine.ConclusionsA single oral dose of bilastine 20 mg had minimal H1RO, was not associated with subjective sedation or objective impairment of psychomotor performance and was devoid of treatment-related sedative AEs, thus satisfying relevant subjective, objective and PET criteria as a non-sedating antihistamine.

Bilastine: a new H1‐antihistamine with an optimal profile for updosing in urticaria

“…More recently similar studies have shown bilastine also had a high efflux ratio . The failure of bilastine and fexofenadine to enter the brain and occupy histamine H 1 ‐receptors has been confirmed using positron emission tomography . It is also important to note that total H 1 ‐receptor occupancy (H 1 RO) in the brain for bilastine and fexofenadine was less than zero.…”

“…43 The failure of bilastine and fexofenadine to enter the brain and occupy histamine H 1receptors has been confirmed using positron emission tomography. 44,45 It is also important to note that total H 1 -receptor occupancy (H 1 RO) in the brain for bilastine and fexofenadine was less than zero. Thus, these two drugs appear to be truly 'nonsedating' H 1 -antihistamines and the most likely reason for their lack of brain penetration is that they are actively pumped out of the blood-brain barrier by P-gp ( Fig.…”

One‐year safety and efficacy study of bilastine treatment in Japanese patients with chronic spontaneous urticaria or pruritus associated with skin diseases

“…dose of bilastine 20 mg did not occupy the H 1 -receptors in the brains. 11 Furthermore, bilastine at therapeutic and supratherapeutic doses (20 and 100 mg once daily, respectively) did not induce any clinically significant changes on QT interval corrected for heart rate prolongation in electrocardiogram, 12 and bilastine requires no dose adjustment in patients with renal dysfunction. 13 In randomized double-blind studies in Japan, the efficacy of 2-week treatment with bilastine 20 mg once daily was superior to that of a placebo in Japanese patients with chronic spontaneous urticaria (CSU) 14 or perennial AR.…”

“…A clinical pharmacological study using positron emission tomography demonstrated that a single p.o. dose of bilastine 20 mg did not occupy the H 1 ‐receptors in the brains . Furthermore, bilastine at therapeutic and supratherapeutic doses (20 and 100 mg once daily, respectively) did not induce any clinically significant changes on QT interval corrected for heart rate prolongation in electrocardiogram, and bilastine requires no dose adjustment in patients with renal dysfunction …”

Safety and tolerability of bilastine 10 mg administered for 12 weeks in children with allergic diseases

“…To date, there has been no evidence of sedative or cardiotoxic effects with bilastine in clinical trials or post‐marketing experience . Bilastine's high selectivity for H 1 receptors , limited passage across the blood–brain barrier and negligible metabolism may confer safety and tolerability advantages over other oral second‐generation H 1 antihistamines used to treat these conditions.…”