Brain histamine H₁ receptor occupancy measured by PET after oral administration of levocetirizine, a non-sedating antihistamine

Abstract

Objective: Histamine H₁ receptor (H₁R) antagonists often have sedative side effects, which are caused by the blockade of the neural transmission of the histaminergic neurons. We examined the brain H₁R occupancy (H₁RO) and the subjective sleepiness of levocetirizine, a new second-generation antihistamine, comparing fexofenadine, another non-sedating antihistamine, as a negative active control.

Methods: Eight healthy volunteers underwent positron emission tomography (PET) imaging with [¹¹C]doxepin, a PET tracer that specifically binds to H₁Rs, after a single oral administration of levocetirizine (5 mg), fexofenadine (60 mg) or placebo in a double-blind crossover study. Binding potential ratios and H₁ROs in the cerebral cortices regions were calculated using placebo. Subjective sleepiness was assessed with the Line Analogue Rating Scale and the Stanford Sleepiness Scale.

Results: There was no significant difference between the mean brain H₁RO after levocetirizine administration (8.1%; 95% CI: −9.8 to 26.0%) and fexofenadine administration (−8.0%; 95% CI: −26.7 to 10.6%). Similarly, subjective sleepiness was not significantly different between the two antihistamines and placebo. Neither subjective sleepiness nor plasma concentrations was significantly correlated with the brain H₁RO of the two antihistamines.

Conclusion: At therapeutic dose, levocetirizine does not bind significantly to the brain H₁Rs and does not induce significant sedation.

Keywords:

• antihistamine
• histamine H₁ receptor occupancy
• levocetirizine
• positron emission tomography
• sedating side effect

Acknowledgments

This study was supported by research funding from GlaxoSmithKline. K Hiraoka did the human PET studies and wrote the manuscript. T Grobosch and M Maurer measured the plasma concentration of levocetirizine and fexofenadine and wrote the manuscript. M Tashiro, K Oda, J Toyohara, K Ishii, and K Ishiwata did the human PET studies. K Yanai designed the study and wrote the manuscript. We appreciate R Boev (Global Medical Affairs, UCB Farchim SA, Switzerland) for discussing the manuscript. The authors also thank Kunpei Hayashi for the radiosynthesis of [¹¹C]doxepin and Hatsumi Endo for supporting PET imaging. This work was supported in part by Grants-in-Aid for Scientific Research from the Japan Society of Technology (‘Molecular Imaging’).

Declaration of interest

K Yanai and M Tashiro have received unrestricted and collaborative research grants support and lecture honoraria from manufactures of the second-generation antihistamines, including Sanofi, GlaxoSmithKline, Kyowa-Kirin and Mitsubishi Tanabe. M Maurer has received lecture honoraria from manufactures of the second-generation antihistamines, including Sanofi, GlaxoSmithKline and UCB. Other authors have no financial conflicts of interest.

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