The long duration of action of the second generation antihistamine bilastine coincides with its long residence time at the histamine H₁ receptor

Drug-target binding kinetics has recently attracted considerable interest in view of the potential predictive power for in vivo drug efficacy. The recently introduced antihistamine bilastine has a long duration of in vivo drug action, which outlasts pharmacological active bilastine concentrations in blood. To provide a molecular basis for the long duration of action, we explored the kinetics of bilastine binding to the human histamine H₁ receptor using [³H]mepyramine binding studies and compared its pharmacodynamics properties to the reference compounds fexofenadine and diphenhydramine, which have a long (60 ± 20 min) and short (0.41 ± 0.1 min) residence time, respectively. Bilastine shows a long drug-target residence time at the H₁ receptor (73 ± 5 min) and this results in a prolonged H₁ receptor antagonism in vitro (Ca²⁺ mobilization in Fluo-4 loaded HeLa cells), following a washout of unbound antagonist. Hence, the long residence time of bilastine can explain the observed long duration of drug action in vivo.