The effect of fluconazole on the steady-state pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine in humans

Abstract

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.

Effect of fluconazole dose on the extent of fluconazole-triazolam interaction

“…The reports about these interactions are controversial, however, and the discrepancies may reflect the dose-dependent nature and large interindividual variation of the fluconazole interactions. In some case reports, fluconazole 100 mg and 200 mg changed cant interaction with the antimycotics ketoconazole and itraconazole [10,11 ]. In the study of Honig et al CYP2C whereas the inhibition of CYP3A mediated metabolism (of midazolam) did not appear to be competitive.…”

Pharmacokinetics and electrocardiographic pharmacodynamics of artemether‐lumefantrine (Riamet®) with concomitant administration of ketoconazole in healthy subjects

“…Co-administration of such potent inhibitors like ketoconazole with other drugs metabolized by CYP3A4 has been reported to lead to potentially highly clinically relevant interactions [22][23][24][25][26][27]41]. Since artemether and lumefantrine are both predominantly metabolized by CYP3A4, this study in healthy volunteers aimed to investigate whether coadministration of ketoconazole could affect the pharmacokinetics of artemether, dihydroartemisinin, and lumefantrine.…”

“…It has been shown to impair the oxidative metabolism of a wide range of clinically used drugs such as antihistamines, immunosuppressives, benzodiazepines and HIV protease inhibitors [18][19][20][21][22]. Clinically significant interactions were reported between ketoconazole and terfenadine or astemizole or tolbutamide leading to QTc interval prolongation and torsade de pointes [23][24][25][26][27].…”

The Implications and Management of Drug Interactions with Itraconazole, Fluconazole and Terbinafine

“…Although its effects on drugs metabolised by CYP3A4 appear to be less widespread than with itraconazole, a number of significant interactions still occur with fluconazole (table 4) [8, 9, 19, 22, 31]. For example, its use with non-sedating antihistamines may be contraindicated [34], while patients receiving gastrointestinal motility agents in addition to the antifungal should be carefully monitored [8, 9, 19]. It may also prove necessary to decrease the dosages of immunosuppressants such as cyclosporin A and tacrolimus when coadministering with fluconazole [8, 9, 35, 36].…”