Brain histamine H¹ receptor occupancy of orally administered antihistamines measured by positron emission tomography with ¹¹ C-doxepin in a placebo-controlled crossover study design in healthy subjects: A comparison of olopatadine and ketotifen

Aims: The strength of sedation due to antihistamines can be evaluated by using positron emission tomography (PET). The purpose of the present study is to measure histamine H₁ receptor (H₁R) occupancy due to olopatadine, a new second-generation antihistamine and to compare it with that of ketotifen. Methods: Eight healthy males (mean age 23.5 years-old) were studied following single oral administration of olopatadine 5 mg or ketotifen 1 mg using PET with ¹¹C-doxepin in a placebo-controlled crossover study design. Binding potential ratio and H₁R occupancy were calculated and were compared between olopatadine and ketotifen in the medial prefrontal (MPFC), dorsolateral prefrontal (DLPFC), anterior cingulate (ACC), insular (IC), temporal (TC), parietal (PC), occipital cortices (OC). Plasma drug concentration was measured, and correlation of AUC to H₁R occupancy was examined. Results: H₁R occupancy after olopatadine treatment was significantly lower than that after ketotifen treatment in the all cortical regions (P < 0.001). Mean H₁R occupancies for olopatadine and ketotifen were, respectively: MPFC, 16.7 vs. 77.7; DLPFC, 14.1 vs. 85.9; ACC, 14.7 vs. 76.1; IC, 12.8 vs. 69.7; TC, 12.5 vs. 66.5; PC, 13.9 vs. 65.8; and OC, 19.5 vs. 60.6. Overall cortical mean H₁R occupancy of olopatadine and ketotifen were 15% and 72%, respectively. H₁R occupancy of both drugs correlated well with their respective drug plasma concentrations (P < 0.001). Conclusion: It is suggested that 5 mg oral olopatadine, with its low H₁R occupancy and thus minimal sedation, could safely be used an antiallergic treatment for various allergic disorders. Abbreviations histamine H₁ receptor (H₁R), histamine H₁ receptor occupancy (H₁RO), dopamine D₂ receptor (D₂R), positron emission tomography (PET), blood-brain barrier (BBB), binding potential ratio (BPR), distribution volume (DV)