Voriconazole drastically increases exposure to oral oxycodone

Eur J Clin Pharmacol. 2009 Mar;65(3):263-71. doi: 10.1007/s00228-008-0568-5. Epub 2008 Oct 3.

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 (AUC(0-infinity)) 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 AUC(0-infinity) 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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Analgesics, Opioid / administration & dosage
  • Analgesics, Opioid / blood
  • Analgesics, Opioid / pharmacokinetics*
  • Antifungal Agents / blood
  • Antifungal Agents / pharmacokinetics
  • Antifungal Agents / pharmacology*
  • Area Under Curve
  • Cross-Over Studies
  • Cytochrome P-450 CYP3A / genetics
  • Cytochrome P-450 CYP3A / metabolism
  • Cytochrome P-450 CYP3A Inhibitors
  • Drug Interactions
  • Enzyme Inhibitors / blood
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Half-Life
  • Humans
  • Male
  • Oxycodone / administration & dosage
  • Oxycodone / blood
  • Oxycodone / pharmacokinetics*
  • Pyrimidines / blood
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology*
  • Triazoles / blood
  • Triazoles / pharmacokinetics
  • Triazoles / pharmacology*
  • Voriconazole

Substances

  • Analgesics, Opioid
  • Antifungal Agents
  • Cytochrome P-450 CYP3A Inhibitors
  • Enzyme Inhibitors
  • Pyrimidines
  • Triazoles
  • Oxycodone
  • Cytochrome P-450 CYP3A
  • Voriconazole