Terfenadine is a nonsedating H1-antagonist that when overdosed, used with hepatic compromise, or when given with ketoconazole results in accumulation of parent terfenadine, prolongation of the QT interval, and torsades de pointes in susceptible patients. Nine subjects were given the recommended dose of terfenadine (60 mg every 12 hours) for 7 days before initiation of oral erythromycin (500 mg every 8 hours). All subjects increased metabolite concentrations after the addition of erythromycin for 1 week. The maximum concentration of metabolite increased by a mean of 107% and the mean metabolite area under the concentration-time curve increased by 170%. Three subjects accumulated unmetabolized terfenadine after administration of erythromycin for 1 week. Electrocardiographic data revealed changes in QT intervals and ST-U complexes in a subset of subjects who accumulated terfenadine. We conclude that erythromycin alters the metabolism of terfenadine, leading to accumulation of terfenadine in certain individuals that is associated with altered cardiac repolarization.

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.

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.

SummaryTerfenadine is a nonsedating histamine HI-antagonist that, when given with ketoconazole, results in accumulation of parent terfenadine and altered cardiac repolarisation in susceptible individuals. This prospective cohort study, designed to assess macrolide effects on terfenadine pharmacokinetics and electrocardiogram (ECG) parameters, evaluated 18 healthy male and female volunteers who received terfenadine to steady-state. Equal numbers (6) were randomised to receive either erythromycin, clarithromycin or azithromycin at recommended doses while continuing terfenadine. Macrolide monotherapy effects on the ECG were also investigated. Pharmacokinetic profiles for terfenadine were performed before and after the addition of macrolide therapy, and ECGs were obtained at baseline and predose on days of blood sampling.Erythromycin and clarithromycin significantly affected the pharmacokinetics of terfenadine. Three of 6 volunteers receiving erythromycin and 4 of 6 receiving clarithromycin demonstrated accumulation of quantifiable un metabolised terfenadine that was associated with altered cardiac repolarisation. Azithromycin had no effect on terfenadine pharmacokinetics or cardiac pharmacodynamics.

Terfenadine is rapidly and nearly completely biotransformed during a first pass to an active acid metabolite. Accumulation of unmetabolized terfenadine has been associated with altered cardiac repolarization. Drug-drug interactions resulting in the accumulation of terfenadine have been reported for ketoconazole and erythromycin. Six subjects were given the recommended dose of terfenadine (60 mg every 12 hours) for 7 days before initiation of oral fluconazole (200 mg once daily). The mean metabolite area under the concentration-time curve increased by 34% and the time to maximum concentration of the metabolite was delayed from 2.3 to 4 hours by concurrent fluconazole. Unmetabolized terfenadine was not present in any subject, and cardiac repolarization was not significantly changed from baseline during any phase of the study. We conclude that a pharmacokinetic interaction between terfenadine and fluconazole exists; however, the absence of accumulation of parent terfenadine in plasma suggests that a clinically significant interaction is unlikely.

No abstract

Solutes and suspended material often experience delays during exchange between phases one of which may be moving. Consequently transport often exhibits combined effects of advection/dispersion, and delays associated with exchange between phases. Such processes are ubiquitous and include transport in porous/fractured media, watersheds, rivers, forest canopies, urban infrastructure systems, and networks. Upscaling approaches often treat the transport and delay mechanisms together, yielding macroscopic “anomalous transport” models. When interaction with the immobile phase is responsible for the delays, it is not the transport that is anomalous, but the lack of it, due to delays. We model such exchanges with a simple generalization of first‐order kinetics completely independent of transport. Specifically, we introduce a remobilization rate coefficient that depends on the time in immobile phase. Memory‐function formulations of exchange (with or without transport) can be cast in this framework, and can represent practically all time‐nonlocal mass balance models including multirate mass transfer and its equivalent counterparts in the continuous time random walk and time‐fractional advection dispersion formalisms, as well as equilibrium exchange. Our model can address delayed single‐/multievent remobilizations as in delay‐differential equations and periodic remobilizations that may be useful in sediment transport modeling. It is also possible to link delay mechanisms with transport if so desired, or to superpose an additional source of nonlocality through the transport operator. This approach allows for mechanistic characterization of the mass transfer process with measurable parameters, and the full set of processes representable by these generalized kinetics is a new open question.

No abstract