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The effect of ingestion time interval on the interaction between itraconazole and triazolam
P J Neuvonen1, A Varhe, K T Olkkola
1Department of Clinical Pharmacology, University of Helsinki, Finland.
Background:
The plasma concentrations and effects of triazolam are markedly increased when it is ingested with itraconazole. The dependence of this interaction on the time interval of their ingestion and the possibility of avoiding the interaction by a correct daily dosing was studied.
Methods:
Ten healthy volunteers took part in this randomized crossover study of five phases, each separated by 4 weeks. The subjects received a single 0.25 mg oral dose of triazolam either without itraconazole or with a single 200 mg dose of itraconazole that was ingested either simultaneously with triazolam or 3, 12, or 24 hours before triazolam. Plasma concentrations of triazolam and itraconazole were determined and pharmacodynamic effects were measured up to 17 hours.
Results:
Itraconazole ingested simultaneously or 3, 12, or 24 hours before triazolam increased the mean area under the triazolam concentration-time curve 3.1-, 4.8-, 4.6-, and 3.8-fold (p < 0.001), respectively. The mean increase in the peak concentration of triazolam ranged from 1.4-fold (taken simultaneously, p < 0.05) to 1.8-fold (3 or 12 hours after itraconazole, p < 0.001). The elimination half-life of triazolam was increased about threefold (p < 0.001) during all itraconazole phases. Pharmacodynamic effects of triazolam were increased along with increased plasma concentrations of triazolam.
Conclusions:
Even a single 200 mg dose of itraconazole interacts considerably with triazolam when this hypnotic agent is ingested within 24 hours after itraconazole. Thus during the daily itraconazole use this interaction cannot be avoided by increasing the time interval between their intake. Furthermore, the risk of interaction is obvious for several days after the cessation of itraconazole therapy.