Emedastine-ketoconazole: pharmacokinetic and pharmacodynamic interactions in healthy volunteers.
OBJECTIVE
To assess the pharmacokinetic and pharmacodynamic interactions of emedastine difumarate, a new antihistamine drug and ketoconazole.


METHODS
Twelve healthy Caucasian volunteers were administered emedastine difumarate 4 mg oral capsules once daily for 10 consecutive days. From day 6 to day 10, ketoconazole 200 mg were co-administered twice daily.


METHODS
The effects of multiple ketoconazole administration on emedastine kinetics were evaluated by comparing values obtained for pharmacokinetic parameters at steady state, with and without ketoconazole. C(ss,max), C(ss,min), tmax, AUCss, t(1/2) and Cl(ss)/F values, obtained after both treatments, were compared. Significant difference was defined as p < 0.05. QTc intervals from ECGs at baseline, after emedastine treatment and after emedastine-ketoconazole co-treatment were statistically compared.


RESULTS
Emedastine steady state pharmacokinetics were slightly altered as a result of the ketoconazole co-treatment. AUCss rose by about 33% (increase ranging from 0.96 to 66.86, 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) was of about 4%. Rate and severity of anti-H 1 sedation episodes also did not increase on ketoconazole co-treatment.


CONCLUSIONS
A moderate, but statistically significant interaction between emedastine and ketoconazole was observed. Pharmacodynamic data indicate no increase in the QTc interval during concomitant therapy. This result is consistent with the multiple emedastine metabolic pathways shown in man which supplement the metabolism by different enzymatic isoforms of CYP450. Concomitant treatment with emedastine and ketoconazole in subjects with normal QT intervals can therefore, be undertaken without special precautions.
Herranz
U
U
Cross Research S.A., Arzo, TI, Switzerland. crossresearch@bluewin.ch
Rusca
A
A
Assandri
A
A
D000293:Adolescent; D000328:Adult; D018926:Anti-Allergic Agents / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000935:Antifungal Agents / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D001562:Benzimidazoles / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D004562:Electrocardiography / Q000187:drug effects; D006801:Humans; D007654:Ketoconazole / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged
D018926:Anti-Allergic Agents; D000935:Antifungal Agents; D001562:Benzimidazoles; D003577:Cytochrome P-450 Enzyme System; C043345:emedastine; D007654:Ketoconazole