Azelastine, an antihistamine with additional pharmacologic properties, was evaluated for a possible influence on pharmacokinetic and electrocardiographic parameters due to its coadministration with CYP3A4 inhibitor ketoconazole (200 mg every 12 hrs). Twelve volunteers entered this 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 azelastine/ketoconazole or azelastine/placebo, and after a 21-day washout period, which was then followed by a 7-day administration of ketoconazole alone. None of the treatments resulted in meaningful alterations of electrocardiographic variables. Pharmacokinetic parameters could not be estimated because ketoconazole metabolites interfered with azelastine assay procedures. In vitro tests with human liver microsomes were used to characterize azelastine's inhibition spectrum. Azelastine did not inhibit CYP3A4 activity but it did inhibit CYP2D6 and CYP2C19 activity with Ki values exceeding maximum plasma concentration by 120 to 800-fold. Therefore, in vitro tests and the absence of electrocardiographic effects suggests azelastine can be safely administered with CYP3A4 inhibitors.