Grapefruit juice alters terfenadine pharmacokinetics resulting in prolongation of repolarization on the electrocardiogram

Objectives: To establish whether the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine are affected by concomitant administration of grapefruit juice and to determine whether any effect of grapefruit juice is dependent on the timing of administration in relation to the dose of terfenadine. Methods: Twelve healthy volunteers were studied in a prospective randomized trial, The primary end points were QT prolongation on the surface electrocardiogram and the pharmacokinetic parameters: area under the concentration-time curve (AUC), maximum concentration, and time to maximum concentration of terfenadine and its acid metabolite terfenadine carboxylate. All subjects received 60 mg terfenadine twice a day with 240 ml water for 7 days, They were then randomized to drink 240 ml of double-strength grapefruit juice simultaneously with terfenadine (simultaneous group) for an additional 7 days or to drink the same dose of grapefruit juice 2 hours after terfenadine for 7 days (delayed group), Twelve timed electrocardiograms and plasma terfenadine and metabolite levels were measured on days 7 and 14, Results: None of the 12 subjects had quantifiable levels of terfenadine when the drug was administered with water, All six subjects who took terfenadine and drank grapefruit juice simultaneously had quanti fiable terfenadine levels, Only two of six who drank grapefruit juice 2 hours after terfenadine had quantifiable levels, The AUC of the acid metabolite increased 55% (p < 0.05) in the simultaneous group and 22% (p = NS) in the delayed group, The mean QT interval increased from 420 to 434 msec (p < 0.05) in the simultaneous group and decreased from 408 to 407 msec (p = NS) in the delayed group. Conclusions: Administration of grapefruit juice concomitantly with terfenadine may lead to an increase in systemic terfenadine bioavailability and result in increases in QT interval, The clinical significance of an increase in QT interval of this magnitude is unclear.