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Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole
A Varhe1, K T Olkkola, P J Neuvonen
1Department of Clinical Pharmacology, University of Helsinki, Finland.
Background:
Triazolam is metabolized by CYP3A4 isozyme. Ketoconazole and itraconazole may seriously interact with some of the substrates of CYP3A4 (e.g., terfenadine); hence their possible interaction with triazolam in humans is important to uncover.
Methods:
In this double-blind, randomized, three-phase crossover study, the interaction between ketoconazole, itraconazole, and triazolam was investigated. Nine healthy young volunteers received either 400 mg ketoconazole, 200 mg itraconazole, or matched placebo (control phase) orally once a day for 4 days. On day 4, each ingested a single 0.25 mg dose of triazolam. Plasma concentrations of triazolam and antimycotics were determined, and pharmacodynamic effects were measured up to 17 hours.
Results:
On average, ketoconazole and itraconazole increased the area under the triazolam concentration-time curve [AUC(0-infinity)] 22-fold and 27-fold (p < 0.001), the peak concentrations threefold (p < 0.001), and the elimination half-life sixfold and sevenfold (p < 0.001), respectively. In seven of the nine subjects, even the maximum concentration of triazolam in plasma was lower without the antimycotics than were the 17-hour concentrations during the ketoconazole and itraconazole phases. All pharmacodynamic effects (e.g., the Digit Symbol Substitution Test) revealed a significant difference between the antimycotic and placebo phases.
Conclusions:
Both ketoconazole and itraconazole seriously affect the pharmacokinetics of triazolam and increase the intensity and duration of its effects. Inhibition of CYP3A4 during the absorption and elimination phases 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.
Insights
Ketoconazole and itraconazole significantly increase triazolam levels and effects by inhibiting CYP3A4. Avoid using triazolam with these antifungals due to potentially hazardous interactions.
Area of Science:
- Pharmacology
- Drug Metabolism
- Clinical Pharmacology
Background:
- Triazolam is metabolized by the CYP3A4 enzyme.
- Ketoconazole and itraconazole are known to interact with CYP3A4 substrates.
- Understanding the interaction between these antifungals and triazolam is crucial.
Purpose of the Study:
- To investigate the pharmacokinetic and pharmacodynamic interaction between ketoconazole, itraconazole, and triazolam.
- To determine the effect of these antifungals on triazolam metabolism and its clinical effects.
Main Methods:
- A double-blind, randomized, three-phase crossover study involving nine healthy volunteers.
- Participants received ketoconazole, itraconazole, or placebo daily for 4 days.
- On day 4, a single dose of triazolam was administered, with plasma concentrations and pharmacodynamic effects measured.
Main Results:
- Ketoconazole and itraconazole increased triazolam's area under the curve 22-fold and 27-fold, respectively.
- Peak triazolam concentrations increased threefold, and elimination half-life extended sixfold to sevenfold.
- Significant differences in pharmacodynamic effects were observed between antifungal and placebo phases.
Conclusions:
- Ketoconazole and itraconazole significantly alter triazolam pharmacokinetics, increasing its effects' intensity and duration.
- CYP3A4 inhibition during triazolam absorption and elimination explains the observed interaction.
- Triazolam should not be co-administered with ketoconazole or itraconazole due to potentially hazardous consequences.