Itraconazole Affects Single‐Dose Terfenadine Pharmacokinetics and Cardiac Repolarization Pharmacodynamics
- 1 December 1993
- journal article
- Published by Wiley in The Journal of Clinical Pharmacology
- Vol. 33 (12), 1201-1206
- https://doi.org/10.1002/j.1552-4604.1993.tb03920.x
Abstract
The object of this study was to examine prospectively the effects of itraconazole on the pharmacokinetics and electrocardiographic repolarization pharmacodynamics (QTc intervals) of single‐dose terfenadine in six healthy volunteers. It was designed as a prospective cohort study with each subject serving as his own control, set in an outpatient cardiology clinic. The participants were six healthy volunteers (two men, four women; ages 24–35) not taking any prescription or over‐the‐counter medications. Single‐dose terfenadine administration (120 mg) was accompanied by pharmacokinetic profiles and serial determination of the QTc interval for 12 hours. The subjects then began daily oral itraconazole (200 mg each morning) for 7 days. Repeat pharmacokinetic and pharmacodynamic determinations were made after administration of a second dose (120 mg) of terfenadine while receiving itraconazole. The main outcome measures were terfenadine and acid metabolite serum concentrations; corrected QT intervals as determined by 12‐lead electrocardiogram (ECG); and presence or absence of late potentials as determined by signal‐averaged ECGs over 150 cardiac cycles. There were significant changes in the pharmacokinetic parameters of acid metabolite after treatment with itraconazole. All subjects had detectable levels of unmetabolized terfenadine after addition of itraconazole, which was associated with QT prolongation. There was no evidence of late depolarization as manifested by an increase in QRS duration found using signal‐averaged electrocardiography. Itraconazole influences the metabolism of terfenadine in normal volunteers and results in the accumulation of unmetabolized parent drug associated with altered cardiac repolarization. This drug combination should be avoided.Keywords
This publication has 16 references indexed in Scilit:
- AN ANALYSIS OF THE TIME‐RELATIONS OF ELECTROCARDIOGRAMS.Annals of Noninvasive Electrocardiology, 1997
- Terfenadine-Ketoconazole InteractionJAMA, 1993
- Comparative effects of the antimycotic drugs ketoconazole, fluconazole, itraconazole and terbinafine on the metabolism of cyclosporin by human liver microsomes.British Journal of Clinical Pharmacology, 1991
- Determination of terfenadine and terfenadine acid metabolite in plasma using solid-phase extraction and high-performance liquid chromatography with fluorescence detectionJournal of Chromatography B: Biomedical Sciences and Applications, 1991
- QTc prolongation measured by standard 12-lead electrocardiography is an independent risk factor for sudden death due to cardiac arrest.Circulation, 1991
- Nifedipine: Variability in its kinetics and metabolism in manPharmacology & Therapeutics, 1989
- TIME COURSE OF CYCLOSPORIN/ITRACONAZOLE INTERACTIONThe Lancet, 1987