Pharmacokinetic-pharmacodynamic analysis of the arrhythmogenic potency of a novel antiallergic agent, ebastine, in rats

Ebastine (EBS), a novel nonsedative antiallergic agent, is similar to terfe nadine in its chemical structure. However, clinical arrhythmogenicity of EB S remains controversial. In this study, we evaluated the possible arrhythmo genic potency of EBS as assessed by QT prolongation from a pharmacokinetic- pharmacodynamic viewpoint in comparison with that of terfenadine. EBS was i ntravenously infused into anesthetized rats at a rate of 3.0 or 10 mg/kg/h for 60 min, and electrocardiographic effects were continuously monitored fr om lead II. The plasma concentrations of EBS and its major metabolite, care bastine, were also measured under the same conditions. When intravenously a dministered, EBS exhibited QT prolongation in an infusion rate-dependent ma nner, with a lag time. Pharmacokinetic-pharmacodynamic analysis of EBS base d on the effect-compartment model revealed values of EC50 E-max and EC10 ms (where 10 ms of QT prolongation was evoked) of 0.73 mu g/mL, 12.5 ms and 2 .90 mu g/mL, respectively. The EC10 (ms) value of EBS was five times higher than that of terfenadine reported previously (Ohtani et al., J. Pharm. Pha rmacol., 49, 458-462 (1997)). In conclusion, EBS was suggested to be less a rrhythmogenic than terfenadine. Copyright (C) 1999 John Wiley & Sons, Ltd.