Voriconazole drastically increases exposure to oral oxycodone

• Published in: European journal of clinical pharmacology Vol. 65; no. 3; pp. 263 - 271
• Main Authors: Hagelberg, Nora M, Nieminen, Tuija H, Saari, Teijo I, Neuvonen, Mikko, Neuvonen, Pertti J, Laine, Kari, Olkkola, Klaus T
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Berlin/Heidelberg : Springer-Verlag 01.03.2009; Springer-Verlag; Springer; Springer Nature B.V; Springer Verlag
• Subjects: administration & dosage; Administration, Oral; Adult; Analgesics, Opioid; Analgesics, Opioid - administration & dosage; Analgesics, Opioid - blood; Analgesics, Opioid - pharmacokinetics; Antifungal Agents; Antifungal Agents - blood; Antifungal Agents - pharmacokinetics; Antifungal Agents - pharmacology; Area Under Curve; Bioavailability; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; blood; Cross-Over Studies; CYP2D6; CYP3A; cytochrome P-450; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A - genetics; Cytochrome P-450 CYP3A - metabolism; Cytochrome P-450 CYP3A Inhibitors; Drug dosages; Drug Interactions; Enzyme Inhibitors; Enzyme Inhibitors - blood; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Female; genetics; Half-Life; Humans; Male; Medical sciences; metabolism; Narcotics; Oxycodone; Oxycodone - administration & dosage; Oxycodone - blood; Oxycodone - pharmacokinetics; pharmacokinetics; Pharmacokinetics and Disposition; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Prescription drugs; Pyrimidines; Pyrimidines - blood; Pyrimidines - pharmacokinetics; Pyrimidines - pharmacology; Triazoles; Triazoles - blood; Triazoles - pharmacokinetics; Triazoles - pharmacology; Voriconazole; CYP3A; Pharmacokinetics; CYP2D6; Oxycodone; Cytochrome P450; Voriconazole; Human; Enzyme; Isozyme; Azole derivatives; Oral administration; Opiates; Exposure; Narcotic analgesic; Antifungal agent; Triazole derivatives
• ISSN: 0031-6970; 1432-1041; 1432-1041
• DOI: 10.1007/s00228-008-0568-5

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₋[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 AUC₀₋[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.