Kaveh Zamani

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

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.

Itraconazole Affects Single‐Dose Terfenadine Pharmacokinetics and Cardiac Repolarization Pharmacodynamics

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.

Comparison of the Effect of the Macrolide Antibiotics Erythromycin, Clarithromycin and Azithromycin on Terfenadine Steady-State Pharmacokinetics and Electrocardiographic Parameters

SummaryTerfenadine is a nonsedating histamine H1-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 unmetabolised terfenadine that was associated with altered cardiac repolarisation. Azithromycin had no effect on terfenadine pharmacokinetics or cardiac pharmacodynamics.

Effect of concomitant administration of cimetidine and ranitidine on the pharmacokinetics and electrocardiographic effects of terfenadine

SummaryTerfenadine is a widely prescribed non-sedating antihistamine which undergoes rapid and almost complete first pass biotransformation to an active carboxylic acid metabolite. It is unusual to find unmetabolised terfenadine in the plasma of patients taking the drug. Terfenadine in vitro is a potent blocker of the myocardial potassium channel. Overdose, hepatic compromise and the coadministration of ketoconazole and erythromycin result in the accumulation of terfenadine, which is thought to be responsible of QT prolongation and Torsades de Pointes ventricular arrhythmia in susceptible individuals. Cimetidine and ranitidine are two popular H2 antagonists which are often taken with terfenadine. The effects of cimetidine and ranitidine on terfenadine metabolism were studied in two cohorts of 6 normal volunteers given the recommended dose of terfenadine (60 mg every 12 h) for 1 week prior to initiation of cimetidine 600 mg every 12 h or ranitidine 150 mg every 12 h. Pharmacokinetic profiles and morning pre-dose electrocardiograms were obtained whilst the patients were on terfenadine alone and after the addition of cimetidine or rantidine.One of the subjects in each cohort had a detectable plasma level of parent compound after 1 week of terfenadine therapy alone; it did not accumulate further after addition of the H2 antagonist. The pharmacokinetics of the carboxylic acid metabolite of terfenadine (Cmax, tmax, AUC) were not significantly changed after co-administration of either H2 antagonist. None of the remaining 5 subjects in either cohort demonstrated accumulation of unmetabolised terfenadine after addition of the respective H2 antagonist and electrocardiographic QT intervals and T-U morphology in them was not changed during the course of the study.We conclude that cimetidine and ranitidine in the dosages used in this study did not affect the metabolism of terfenadine, and that patients exposed to these drug combinations are not at increased risk of altered cardiac repolarisation.

Transcutaneous theophylline collection in preterm infants

Transcutaneous collection of theophylline and its metabolite, caffeine, was undertaken in 33 preterm infants (2 to 89 days old) who were receiving routine theophylline therapy. Collection was done by means of a novel adhesive transcutaneous collection system. The transcutaneous collection system accumulated substances that migrated from the blood to the skin surface by trapping them in an activated charcoal‐gel matrix. On one to three occasions, four transdermal collection systems were applied to the back or abdomen of each infant for 4 to 12 hours. During that time, blood samples were obtained for routine monitoring of plasma theophylline levels. Amounts of theophylline (95 ± 198 ng) and caffeine (83 ± 77 ng) in the transcutaneous collection system were significantly correlated with the respective average plasma drug concentration and postconceptional age (p < 0.01). Skin reactions were limited to mild erythema. We concluded that theophylline and caffeine can be collected on the surface of the skin of preterm infants with a novel transcutaneous collection system. Amounts collected by means of the transcutaneous collection system correlated with plasma concentrations consistent with a diffusion process, but they were poor predictors of individual concentrations.

Transcutaneous Collection of Theophylline: Constancy and Linearity of Skin Permeability

Transcutaneous chemical collection is a novel method for noninvasive collection and measurement of body exposure to chemicals using a transcutaneous collection device (TCD) consisting of a circular adhesive-tape-encased saline-activated carbon-aquagel patch. The objectives of this study were to determine (1) the time-course of skin permeability change after the placement of a TCD on the skin, and (2) the relationship between the amount of theophylline collected in a TCD and the amount of theophylline in the body as expressed by the area under the plasma concentration-time curve (AUC). Skin permeability changes were determined by emplacing TCDs (24/monkey) on the chests and abdomens of female rhesus monkeys (12 studies in 4 monkeys) at 48, 24, 6, 3 and 1 h prior to dosing with aminophylline (10 mg/kg of theophylline, i.v.) over 30 min. Several blood samples were collected, and TCDs were removed at 24 h post-dose; samples were assayed for theophylline by HPLC. The apparent permeability coefficients (Kp) increased following TCD placement reaching 90% of maximum by 17 h. The relationship between the amount of theophylline collected in the device (Q) and amount in the body over time was determined by emplacing TCDs on rhesus monkeys (8 studies in 4 monkeys) 24 h prior to administration of 10 mg/kg of theophylline. Qs from the TCDs removed at 0.17, 0.5, 1, 3, 6 and 24 h were linearly related to the plasma AUC according to the relationship: Q = (A x Kp) x AUC, where A is the area of gel in contact with the skin for each TCD.