ORAL TRIAZOLAM IS POTENTIALLY HAZARDOUS TO PATIENTS RECEIVING SYSTEMIC ANTIMYCOTICS KETOCONAZOLE OR ITRACONAZOLE

Background: Triazolam is metabolized by CYP3A4 isozyme. Ketoconazole a nd itraconazole may seriously interact with some of the substrates of CYP3A4 (e.g., terfenadine); hence their possible interaction with tria zolam in humans is important to uncover. Methods: In this double-blind , randomized three-phase crossover study, the interaction between keto conazole, itraconazole, and triazolam was investigated. Nine healthy y oung volunteers received either 400 mg ketoconazole, 200 mg itraconazo le, or matched placebo (control phase) orally once a day for 4 days. O n day 4, each ingested a single 0.25 mg dose of triazolam. Plasma conc entrations of triazolam and antimycotics were determined, and pharmaco dynamic effects were measured up to 17 hours. Results: On average, ket oconazole and itraconazole increased the area under the triazolam conc entration-time curve [AUC(0-infinity)] 22-fold and 27-fold (P < 0.001) , the peak concentrations threefold (p < 0.001), and the elimination h alf-life sixfold and sevenfold (p < 0.001), respectively. In seven of the nine subjects; even the maximum concentration of triazolam in plas ma was lower without the antimycotics than were the 17-hour concentrat ions during the ketoconazole and itraconazole phases. All pharmacodyna mic effects (e.g., the Digit Symbol Substitution Test) revealed a sign ificant difference between the antimycotic and placebo phases. Conclus ions: Bath ketoconazole and itraconazole seriously affect the pharmaco kinetics of triazolam and increase the intensity and duration of its e ffects. Inhibition of CYP3A4 during the absorption and elimination pha ses of triazolam seems to explain the interaction observed. Because of the potentially hazardous consequences of this interaction, triazolam should be avoided if patients are using ketoconazole or itraconazole.