Pharmacokinetic modeling of the dosing interval dependency for the interaction between itraconazole and triazolam.
OBJECTIVE
Itraconazole is a potent inhibitor of cytochrome P450 (CYP) 3A with an elimination half-life of more than 30 hours. Therefore, itraconazole may cause persistent CYP3A inhibition. Triazolam is primarily metabolized by CYP3A and its plasma concentration is increased remarkably by itraconazole. Although separating their dosages by 24 hours has been shown to reduce the interaction, an appropriate dosage interval remains to be determined. The aim of this study was to identify an appropriate dosage schedule to avoid their interaction.


METHODS
We developed a pharmacokinetic model based on the assumption that both itraconazole and hydroxyitraconazole competitively and reversibly inhibit the first-pass metabolism and systemic elimination of triazolam. The developed model was simultaneously fitted to the plasma concentration profiles of triazolam, taken from the literature, by using the plasma concentration-time profiles of itraconazole and hydroxyitraconazole as input functions to estimate their in vivo Ki values. Subsequently, we simulated the plasma concentration profiles of triazolam administered after itraconazole therapy with various dosing intervals.


RESULTS
The model could explain and simulate the interaction between itraconazole-triazolam using a variety of dosage intervals between the administrations.


CONCLUSIONS
The developed model may provide useful information with regard to the appropriate interval for triazolam administration during itraconazole therapy.
Toi
A
A
Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Tokyo, Japan.
Ohtani
H
H
Tsujimoto
M
M
Sawada
Y
Y
D000284:Administration, Oral; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004334:Drug Administration Schedule; D004347:Drug Interactions; D006801:Humans; D017964:Itraconazole / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000494:pharmacology; D008954:Models, Biological; D013997:Time Factors; D014229:Triazolam / Q000008:administration & dosage / Q000493:pharmacokinetics*
D014151:Anti-Anxiety Agents; D000935:Antifungal Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; C084794:hydroxyitraconazole; D014229:Triazolam; D017964:Itraconazole; D051544:Cytochrome P-450 CYP3A