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Effects of itraconazole on the pharmacokinetics and pharmacodynamics of intravenously and orally administered oxycodone

  • Pharmacokinetics and Disposition
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Abstract

Background

The aim of this study was to investigate the effects of the cytochrome P450 3A4 (CYP34A) inhibitor itraconazole on the pharmacokinetics and pharmacodynamics of orally and intravenously administered oxycodone.

Methods

Twelve healthy subjects were administered 200 mg itraconazole or placebo orally for 5 days in a four-session paired cross-over study. On day 4, oxycodone was administered intravenously (0.1 mg/kg) in the first part of the study and orally (10 mg) in the second part. Plasma concentrations of oxycodone and its oxidative metabolites were measured for 48 h, and pharmacodynamic effects were evaluated.

Results

Itraconazole decreased plasma clearance (Cl) and increased the area under the plasma concentration–time curve (AUC0–∞) of intravenous oxycodone by 32 and 51%, respectively (P < 0.001) and increased the AUC(0–∞) of orally administrated oxycodone by 144% (P < 0.001). Most of the pharmacokinetic changes in oral oxycodone were seen in the elimination phase, with modest effects by itraconazole on its peak concentration, which was increased by 45% (P = 0.009). The AUC(0–48) of noroxycodone was decreased by 49% (P < 0.001) and that of oxymorphone was increased by 359% (P < 0.001) after the administration of oral oxycodone. The pharmacologic effects of oxycodone were enhanced by itraconazole only modestly.

Conclusions

Itraconazole increased the exposure to oxycodone by inhibiting its CYP3A4-mediated N-demethylation. The clinical use of itraconazole in patients receiving multiple doses of oxycodone for pain relief may increase the risk of opioid-associated adverse effects.

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Acknowledgements

We want to thank Mrs. Elina Kahra (Medical laboratory technologist, Clinical Pharmacology, TYKSLAB, Hospital District of Southwest Finland, Turku, Finland) for her skillful technical assistance.

Financial Support

Turku University Hospital research fund EVO 13821, Turku, Finland; Finnish Society of Anaesthesiologists, Helsinki, Finland; Finnish Association for the Study of Pain, Helsinki, Finland and Sigfrid Juselius Foundation, Helsinki, Finland

Conflict of Interest

None

Author information

Authors and Affiliations

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

    Teijo I. Saari, Juha Grönlund, Nora M. Hagelberg & Klaus T. Olkkola

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

    Mikko Neuvonen & Pertti J. Neuvonen

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

    Kari Laine

Authors
  1. Teijo I. Saari
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  2. Juha Grönlund
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  3. Nora M. Hagelberg
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  4. Mikko Neuvonen
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  7. Klaus T. Olkkola
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Correspondence to Teijo I. Saari.

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Saari, T.I., Grönlund, J., Hagelberg, N.M. et al. Effects of itraconazole on the pharmacokinetics and pharmacodynamics of intravenously and orally administered oxycodone. Eur J Clin Pharmacol 66, 387–397 (2010). https://doi.org/10.1007/s00228-009-0775-8

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  • DOI: https://doi.org/10.1007/s00228-009-0775-8

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