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Voriconazole and fluconazole increase the exposure to oral diazepam

  • Pharmacokinetics and Disposition
  • Published:
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Abstract

Objective

We assessed the effect of voriconazole and fluconazole on the pharmacokinetics and pharmacodynamics of diazepam.

Methods

Twelve healthy volunteers took 5 mg of oral diazepam in a randomised order on three study sessions: without pretreatment, after oral voriconazole 400 mg twice daily on the first day and 200 mg twice daily on the second day, or after oral fluconazole 400 mg on the first day and 200 mg on the second day. Plasma concentrations of diazepam and N-desmethyldiazepam were determined for up to 48 h. Pharmacodynamic variables were measured for 12 h.

Results

In the voriconazole phase, the area under the plasma concentration time curve \( {\left( {{\text{AUC}}_{{{\text{0 - }}\infty }} } \right)} \) of diazepam was increased (geometric mean ratio) 2.2-fold (p < 0.05; 90% confidence interval [CI] 1.56 to 2.82). This was associated with the prolongation of the mean elimination half-life (t1/2) from 31 h to 61 h (p < 0.01) after voriconazole. In the fluconazole phase, the \( {\text{AUC}}_{{{\text{0 - }}\infty }} \) of diazepam was increased 2.5-fold (p < 0.01; 90% CI 1.94 to 3.40), and the t1/2 was prolonged from 31 h to 73 h (p < 0.001). The peak plasma concentration of diazepam was practically unchanged by voriconazole and fluconazole. The pharmacodynamics of diazepam were changed only modestly.

Conclusion

Both voriconazole and fluconazole considerably increase the exposure to diazepam. Recurrent administration of diazepam increases the risk of clinically significant interactions during voriconazole or fluconazole treatment, because the elimination of diazepam is impaired significantly.

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Acknowledgements

We thank Mrs. Elina Kahra, Mrs. Eija Mäkinen-Pulli and Mr. Jouko Laitila for technical assistance and skilful determinations of the drug plasma concentrations. The study was supported by the EVO grants #13821 and # 13390 of the Hospital District of Southwest Finland; the Duodecim Foundation; the Sigrid Juselius Foundation and the Swedish Council, Medicine (3902). All experiments comply with the current laws in Finland, where the research was performed. There are no conflicts of interest.

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Authors and Affiliations

  1. Department of Anesthesiology, Intensive Care, Emergency Care and Pain Medicine, University of Turku, P.O. Box 52, Kiinamyllynkatu 4-8, 20520, Turku, Finland

    Teijo I. Saari & Klaus T. Olkkola

  2. Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland

    Kari Laine

  3. Division of Clinical Pharmacology at Karolinska Institute, Department of Laboratory Medicine, Huddinge University Hospital, Stockholm, Sweden

    Leif Bertilsson

  4. Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland

    Pertti J. Neuvonen

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  1. Teijo I. Saari
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Correspondence to Teijo I. Saari.

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Saari, T.I., Laine, K., Bertilsson, L. et al. Voriconazole and fluconazole increase the exposure to oral diazepam. Eur J Clin Pharmacol 63, 941–949 (2007). https://doi.org/10.1007/s00228-007-0350-0

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  • DOI: https://doi.org/10.1007/s00228-007-0350-0

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