Brain histamine H1 receptor occupancy of orally administered antihistamines, bepotastine and diphenhydramine, measured by PET with 11C-doxepin

AIMS

Antihistamines are frequently used for treating various allergic diseases, but often induce sedation. The degree of sedation can be evaluated by measuring histamine H₁ receptor occupancy (H₁RO) in the brain using positron emission tomography (PET). The aim was to measure H₁RO of bepotastine, a new second-generation antihistamine, and to compare it with that of diphenhydramine.

METHODS

Eight healthy male volunteers (mean age ± SD 24.4 ± 3.3 years) were studied after single oral administration of bepotastine (10 mg), diphenhydramine (30 mg) or placebo, by PET imaging with ¹¹C-doxepin in a crossover study design. Binding potential ratio and H₁ROs were calculated using placebo data and were compared between bepotastine and diphenhydramine in the anterior and posterior cingulate gyri (ACG and PCG, respectively), superior and inferior frontal cortices (SFC and IFC, respectively), orbitofrontal cortex (OFC), insular cortex (IC), lateral and medial temporal cortices (LTC and MTC, respectively), parietal cortex (PC), occipital cortex (OC) and sensorimotor cortex (SMC). Plasma concentration of each antihistamine was measured, and its correlation to H₁RO was examined.

RESULTS

H₁RO after bepotastine treatment was significantly lower than that after diphenhydramine treatment in all cortical regions (P < 0.001). Mean H₁ROs of bepotastine and diphenhydramine were 14.7% and 56.4%, respectively. H₁ROs of both bepotastine and diphenhydramine correlated to their respective drug plasma concentration (P < 0.001).

CONCLUSION

Oral bepotastine (10 mg), with its relatively low H₁RO and thus minimal sedation, has the potential for use as a mildly or slightly sedative antihistamine in the treatment of various allergic disorders.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• ‘Bepotastine besilate’ is a novel second-generation antihistamine developed in Japan and its antiallergic effects have already been demonstrated by various studies.
• However, only a few clinical studies regarding its sedative property are available.
• In addition, histamine H₁ receptor occupancy (H₁RO) of this new antihistamine has never been measured by positron emission tomography (PET).

WHAT THIS STUDY ADDS

• This paper provides the first measurement result of cerebral H₁RO of bepotastine besilate (approximately 15%) as determined by PET.
• This result is in accordance with the clinical classification of bepotastine as a second-generation antihistamine.
• In addition, the relationship between subjective sleepiness and cerebral H₁RO of this second-generation antihistamine is demonstrated for the first time using a placebo-controlled crossover study design.