Pharmacokinetic modeling of the dosing interval dependency for the interaction between itraconazole and triazolam

A. Toi, H. Ohtani, M. Tsujimoto, Y. Sawada

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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. Materials and 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 fromthe 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.

Original languageEnglish
Pages (from-to)356-366
Number of pages11
JournalInternational Journal of Clinical Pharmacology and Therapeutics
Volume48
Issue number6
DOIs
Publication statusPublished - 2010 Jun

Keywords

  • CYP3A4
  • Cytochrome P450
  • Dosage regimen
  • Drug interaction
  • Time-dependent inhibition

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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