Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin

Abstract

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.

Evidence-based absorption, distribution, metabolism, excretion (ADME) and its interplay with alternative toxicity methods

“…In real clinical situations, however, terfenadine was frequently co-administered with the CYP 3A4 inhibitors ketoconazole or erythromycin (Honig et al, 1993). Blocking the metabolism of terfenadine caused over-exposure of patients, leading to increases in plasma terfenadine to levels that caused cardiac toxicity (Honig et al, 1992). The resulting withdrawal of the drug from the market (FDA, 2009) cost an estimated $6 billion.…”

General medicine and surgery for dental practitioners Part 2: Respiratory system

“…Hydrocortisone and methylprednisolone have been shown to both increase and decrease theophylline levels. Terfenadine decreases the plasma concentration of erythromycin 8 and this may be clinically important.…”

“…Stevens-Johnson syndrome may occur. Tricyclic and mono-amine oxidase inhibitor antidepres- Table 3 Relevant features on examination of a dental patient with respiratory disease which may be present Among the many drugs which may produce dangerous arrythmias when combined with terfenadine are erythromycin, 8 the anti fungal drugs, miconazole, fluconazole, itraconazole and ketoconazole 9 and the antiviral agents efavirenz, indinavir, nelfinavir, ritonavir and saquinavir. Grapefruit juice must be avoided during therapy with terfenadine to avoid arrhythmias.…”

De-Risking Drug Discovery Programmes Early with ADMET

“…By the late 1990s the pharmaceutical industry recognized the value of early ADMET assessment and began routinely employing it with noticeable results. ADME and DMPK problems decreased from 40% to 11% (4). Presently, a lack of efficacy and human toxicity are the primary reasons for failure (11).…”

“…For example, terfenadine is both a potent hERG cardial channel ligand and is metabolized by the liver enzyme Cyp3A4. Terfenadine was frequently co-administered with Cyp3A4 inhibitors ketoconazole or erythromycin (4). The consequent overload resulted in increases in plasma terfenadine to levels that caused cardiac toxicity (5) resulting in the drug to be withdrawn from the market (6) at an estimated cost of $6 billion USD.…”