LACK OF EFFECT OF AZELASTINE AND KETOCONAZOLE COADMINISTRATION ON ELECTROCARDIOGRAPHIC PARAMETERS IN HEALTHY-VOLUNTEERS

Azelastine, an antihistamine with additional pharmacologic properties, was evaluated for a possible influence on pharmacokinetic and electro cardiographic parameters due to its coadministration with CYP3A4 inhib itor ketoconazole (200 mg every 12 hrs). Twelve volunteers entered thi s three-period, open-label study. Electrocardiographic parameters (PR, QRS and QTc intervals and U-wave morphology) were monitored after 14 days of azelastine HCl (4.4 mg every 12 hrs), after 7 days of either a zelastine/ ketoconazole or azelastine/placebo, and after a 21-day wash out period, which was then followed by a 7-day administration of ketoc onazole alone. None of the treatments resulted in meaningful alteratio ns of electrocardiographic variables. Pharmacokinetic parameters could not be estimated because ketoconazole metabolites interfered with aze lastine assay procedures. In vitro tests with human liver microsomes w ere used to characterize azelastine's inhibition spectrum. Azelastine did not inhibit CYP3A4 activity but it did inhibit CYP2D6 and CYP2C19 activity with K-i values exceeding maxim um plasma concentration by 12 0 to 800-fold. Therefore, in vitro tests and the absence of electrocar diographic effects suggests azelastine can be safely administered with CYP3A4 inhibitors.