Voriconazole drastically increases exposure to oral oxycodone.
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.
Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine, Turku University Hospital, PO Box 52 (Kiinamyllynkatu 4-8), FI-20521 Turku, Finland.
Nora M
NM
Hagelberg
Tuija H
TH
Nieminen
Teijo I
TI
Saari
Mikko
M
Neuvonen
Pertti J
PJ
Neuvonen
Kari
K
Laine
Klaus T
KT
Olkkola
D000284:Administration, Oral; D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000935:Antifungal Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D010098:Oxycodone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D014230:Triazoles / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D065819:Voriconazole
D000701:Analgesics, Opioid; D000935:Antifungal Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D014230:Triazoles; D010098:Oxycodone; D051544:Cytochrome P-450 CYP3A; D065819:Voriconazole