ITRACONAZOLE AFFECTS SINGLE-DOSE TERFENADINE PHARMACOKINETICS AND CARDIAC REPOLARIZATION PHARMACODYNAMICS

The object of this study was to examine prospectively the effects of i traconazole on the pharmacokinetics and electrocardiographic repolariz ation pharmacodynamics (QTc intervals) of single-dose terfenadine in s ix healthy volunteers. It was designed as a prospective cohort study w ith each subject serving as his own control, set in an outpatient card iology clinic. The participants were six healthy volunteers (two men, four women; ages 24-35) not taking any prescription or over-the-counte r medications. Single-dose terfenadine administration (120 mg) was acc ompanied by pharmacokinetic profiles and serial determination of the Q Tc interval for 12 hours. The subjects then began daily oral itraconaz ole (200 mg each morning) for 7 days. Repeat pharmacokinetic and pharm acodynamic determinations were made after administration of a second d ose (120 mg) of terfenadine while receiving itraconazole. The main out come measures were terfenadine and acid metabolite serum concentration s; corrected QT intervals os determined by 12-lead electrocardiogram ( ECG); and presence or absence of late potentials as determined by sign al-averaged ECGs over 150 cardiac cycles. There were significant chang es in the pharmacokinetic parameters of acid metabolite after treatmen t with itraconazole. All subjects had detectable levels of unmetaboliz ed terfenadine after addition of itraconazole, which was associated wi th QT prolongation. There was no evidence of late depolarization as ma nifested by an increase in QRS duration found using signal-averaged el ectrocardiography. Itraconazole influences the metabolism of terfenadi ne in normal volunteers and results in the accumulation of unmetaboliz ed parent drug associated with altered cardiac repolarization. This dr ug combination should be avoided.