A current appraisal of drug interactions of significance in clinical practice: focus on antifungal therapeutic agents used in the treatment of superficial mycoses

Abstract

The subject of drug-drug interactions has continued to expand in terms of understanding its mechanisms, with potentially significant interactions based on advances in evaluating metabolic pathways and enhanced recognition of the importance of pharmacogenomics. Within dermatology, the clinical significance of drug interactions has been made evident by the withdrawal from the marketplace of the “nonsedating” antihistamines, terfenadine and astemizole, due to the increased propensity for prolongation of the QTc interval with subsequent ventricular arrhythmia when these agents were coadministered with erythromycin, ketoconazole or itraconazole. This “hallmark interaction” association is directly related to inhibition of the cytochrome (CYP) 3A4 metabolic pathway by several macrolide antibiotics and azole antifungal agents. Due to the predominant role of CYP 3A4 in the metabolism of approximately half of currently available drugs, the potential for widespread impact related to CYP3A4 inhibition, as well as other less predominant CYP metabolic isoenzymes, has received significant notoriety. In the US, between 1987 and 1991, 98 drugs received approval for use with 32 inclusive of drug interaction studies. Between 1992 and 1997, although the number of approved drugs doubled, the number of associated drug interaction studies more than tripled. Several warnings and contraindications have emerged related to drug interactions, such as recommendations to avoid coadministration of some macrolide antibiotics or azole antifungal agents with HMG-CoA reductase inhibitors, some benzodiazepines and some cardiac drugs, including digoxin. Considering the widespread prevalence of superficial mycotic infections and associated oral antifungal use, it is rational to periodically revisit the subject of potential drug interactions and oral antifungal agents. Due to variations in metabolic pathways, significant differences in the potential for interactions have been established when comparing griseofulvin, terbinafine, ketoconazole and the triazoles, itraconazole and fluconazole. Overall, compared to other oral antifungal agents, terbinafine is associated with the most favorable safety profile with regard to clinically significant drug interactions. This poster provides an overview and update on potential drug interactions related to the selection of specific oral antifungal agents. Emphasis will be placed on supportive data, clinical significance, and management suggestions for the clinician.