Emedastine-ketoconazole: pharmacokinetic and pharmacodynamic interactions in healthy volunteers

Objective: To assess the pharmacokinetic and pharmacodynamic interactions o f emedastine difumarate, a new, antihistamine drug and ketoconazole. Materi al: Twelve healthy Caucasian volunteers were administered emedastine difuma rate 4 mg oral capsules once daily for 10 consecutive days. From day 6 to d ay 10, ketoconazole 200 mg were co-administered twice daily. Methods: The e ffects of multiple ketoconazole administration on emedastine kinetics were evaluated by comparing values obtained for pharmacokinetic parameters at st eady state, with and without ketoconazole. C-ss,C-max, C-ss,C-min, t(max), AUC(ss), t(1/2) and Cl-ss/F values, obtained after both treatments, were co mpared. Significant difference was defined as p < 0.05. QTc intervals from ECGs at baseline, after emedastine treatment and after emedastine-ketoconaz ole co-treatment were statistically compared. Results: Emedastine steady st ate pharmacokinetics were slightly altered as a result of the ketoconazole co-treatment. AUC(ss) rose by about 33% (increase ranging from 0.96 to 66.8 6, p < 0.001) and total clearance decreased by about 30% (ranging from 0.96 to 40.08, p < 0.001) with no change in the half-life. These events did not lead to relevant pharmacodynamic changes, i.e. maximum prolongation of the corrected QT interval (QTc) observed after 5 days co-treatment (day 10) wa s of about 4%. Rate and severity of anti-H-1 sedation episodes also did not increase on ketoconazole co-treatment. Conclusions: A moderate, but statis tically significant interaction between emedastine and ketoconazole was obs erved. Pharmacodynamic data indicate no increase in the QTc interval during concomitant therapy. This result is consistent with the multiple emedastin e metabolic pathways shown in man which supplement the metabolism by differ ent enzymatic isoforms of CYP450. Concomitant treatment with emedastine and ketoconazole in subjects with normal QT intervals can therefore, be undert aken without special precautions.