THE EFFECT OF FLUCONAZOLE ON THE STEADY-STATE PHARMACOKINETICS AND ELECTROCARDIOGRAPHIC PHARMACODYNAMICS OF TERFENADINE IN HUMANS

Terfenadine is rapidly and nearly completely biotransformed during a f irst pass to an active acid metabolite. Accumulation of unmetabolized terfenadine has been associated with altered cardiac repolarization. D rug-drug interactions resulting in the accumulation of terfenadine hav e been reported for ketoconazole and erythromycin. Six subjects were g iven the recommended dose of terfenadine (60 mg every 12 hours) for 7 days before initiation of oral fluconazole (200 mg once daily). The me an metabolite area under the concentration-time curve increased by 34% and the time to maximum concentration of the metabolite was delayed f rom 2.3 to 4 hours by concurrent fluconazole. Unmetabolized terfenadin e was not present in any subject, and cardiac repolarization was not s ignificantly changed from baseline during any phase of the study. We c onclude that a pharmacokinetic interaction between terfenadine and flu conazole exists; however, the absence of accumulation of parent terfen adine in plasma suggests that a clinically significant interaction is unlikely.