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Voriconazole drastically increases exposure to oral oxycodone

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Objective

We investigated the effect of voriconazole on the pharmacokinetics and pharmacodynamics of oxycodone.

Methods

Twelve healthy subjects ingested either voriconazole or placebo for 4 days in a randomized, cross-over study. On day 3, they ingested 10 mg oxycodone. Timed plasma samples were collected for the measurement of oxycodone, noroxycodone, oxymorphone, noroxymorphone and voriconazole up to 48 h, and pharmacodynamic effects were recorded.

Results

When voriconazole was taken at the same time as oxycodone, the mean area under the plasma concentration-time curve (AUC0–∞) of oxycodone increased 3.6-fold (range 2.7- to 5.6-fold), peak plasma concentration 1.7-fold and elimination half-life 2.0-fold (p < 0.001) when compared to placebo. The AUC0-∞ ratio of noroxycodone to oxycodone was decreased by 92% (p < 0.001), and that of oxymorphone increased by 108% (p < 0.01). Pharmacodynamic effects of oxycodone were modestly increased by voriconazole.

Conclusions

Voriconazole inhibits the CYP3A-mediated N-demethylation of oxycodone, drastically increasing exposure to oral oxycodone. Clinically, lower doses of oxycodone may be needed during voriconazole treatment to avoid opioid-related adverse effects especially after repeated dosing.

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Acknowledgements

We thank Mrs. Elina Kahra for technical assistance and Professor Antti Pertovaara for the use of the TSA-2. The study was supported by the EVO grant 13821 of the Hospital District of Southwest Finland. 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 Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine, Turku University Hospital, P.O. Box 52 (Kiinamyllynkatu 4–8), FI-20521, Turku, Finland

    Nora M. Hagelberg, Tuija H. Nieminen, Teijo I. Saari & Klaus T. Olkkola

  2. Department of Clinical Pharmacology, University of Helsinki, P.O. Box 705, FI-00029, Helsinki, Finland

    Mikko Neuvonen & Pertti J. Neuvonen

  3. Department of Pharmacology, Drug Development & Therapeutics, University of Turku, Itäinen pitkäkatu 4, FI-20520, Turku, Finland

    Kari Laine

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  1. Nora M. Hagelberg
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  2. Tuija H. Nieminen
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  3. Teijo I. Saari
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  4. Mikko Neuvonen
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Correspondence to Klaus T. Olkkola.

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Hagelberg, N.M., Nieminen, T.H., Saari, T.I. et al. Voriconazole drastically increases exposure to oral oxycodone. Eur J Clin Pharmacol 65, 263–271 (2009). https://doi.org/10.1007/s00228-008-0568-5

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  • DOI: https://doi.org/10.1007/s00228-008-0568-5

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