Oxycodone concentrations are greatly increased by the concomitant use of ritonavir or lopinavir/ritonavir.

PURPOSE: this study aimed to investigate the effect of antivirals ritonavir and lopinavir/ritonavir on the pharmacokinetics and pharmacodynamics of oral oxycodone, a widely used opioid receptor agonist used in the treatment of moderate to severe pain. METHODS: a randomized crossover study design with three phases at intervals of 4 weeks was conducted in 12 healthy volunteers. Ritonavir 300 mg, lopinavir/ritonavir 400/100 mg, or placebo b.i.d. for 4 days was given to the subjects. On day 3, 10 mg oxycodone hydrochloride was administered orally. Plasma concentrations of oxycodone, noroxycodone, oxymorphone, and noroxymorphone were determined for 48 h. Pharmacokinetic parameters were calculated with standard noncompartmental methods. Behavioral effects and experimental cold pain analgesia were assessed for 12 h. ANOVA for repeated measures was used for statistical analysis. RESULTS: ritonavir and lopinavir/ritonavir increased the area under the plasma concentration-time curve of oral oxycodone by 3.0-fold (range 1.9- to 4.3-fold; P <0.001) and 2.6-fold (range 1.9- to 3.3-fold; P <0.001). The mean (± SD) elimination half-life increased after ritonavir and lopinavir/ritonavir from 3.6 ± 0.6 to 5.6 ± 0.9 h (P <0.001) and 5.7 ± 0.9 h (P <0.001), respectively. Both ritonavir (P <0.001) and lopinavir/ritonavir (P <0.05) increased the self-reported drug effect of oxycodone. CONCLUSIONS: ritonavir and lopinavir/ritonavir greatly increase the plasma concentrations of oral oxycodone in healthy volunteers and enhance its effect. When oxycodone is used clinically in patients during ritonavir and lopinavir/ritonavir treatment, reductions in oxycodone dose may be needed to avoid opioid-related adverse effects.

Rifampin greatly reduces the plasma concentrations of intravenous and oral oxycodone.

BACKGROUND: Oxycodone is a mu-opioid receptor agonist that is metabolized mainly in the liver by cytochrome P450 3A and 2D6 enzymes. Rifampin is a strong inducer of several drug-metabolizing enzymes. The authors studied the interaction of rifampin with oxycodone. Their hypothesis was that rifampin enhances the CYP3A-mediated metabolism of oxycodone and attenuates its pharmacologic effect. METHODS: The protocol was a four-session, paired crossover. Twelve volunteers were given 600 mg oral rifampin or placebo once daily for 7 days. Oxycodone was given on day 6. In the first part of the study, 0.1 mg/kg oxycodone hydrochloride was given intravenously. In the second part of the study, 15 mg oxycodone hydrochloride was given orally. Concentrations of oxycodone and its metabolites noroxycodone, oxymorphone, and noroxymorphone were determined for 48 h. Psychomotor effects were characterized for 12 h by several visual analog scales. Analgesic effects were characterized by measuring the heat pain threshold and cold pain sensitivity. RESULTS: Rifampin decreased the area under the oxycodone concentration-time curve of intravenous and oral oxycodone by 53% and 86%, respectively (P < 0.001). Oral bioavailability of oxycodone was decreased from 69% to 21% (P < 0.001). Rifampin greatly increased the plasma metabolite-to-parent drug ratios for noroxycodone and noroxymorphone (P < 0.001). Pharmacologic effects of oral oxycodone were attenuated. CONCLUSIONS: Induction of cytochrome P450 3A by rifampin reduced the area under the oxycodone concentration-time curve of intravenous and oral oxycodone. The pharmacologic effects of oxycodone were modestly attenuated. To maintain adequate analgesia, dose adjustment of oxycodone may be necessary, when used concomitantly with rifampin.

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.

Grapefruit juice enhances the exposure to oral oxycodone.

Grapefruit juice alters the concentrations of many CYP3A substrates. The objective of this study was to examine the effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of oral oxycodone in a randomized cross-over study with two phases at an interval of 4 weeks. Twelve healthy volunteers ingested 200 ml of grapefruit juice or water t.i.d. for 5 days. An oral dose of oxycodone hydrochloride 10 mg was administered on day 4. Oxycodone, noroxycodone, oxymorphone and noroxymorphone concentrations were analysed from the plasma samples for 48 hr and behavioural and analgesic effects were recorded for 12 hr. Grapefruit juice increased the mean area under the oxycodone concentration-time curve (AUC(0-∞) ) by 1.7-fold (p<0.001), the peak plasma concentration by 1.5-fold (p<0.001) and the half-life of oxycodone by 1.2-fold (p<0.001) as compared to the water. The metabolite-to-parent AUC(0-∞) ratios (AUC(m)/AUC(p) ) of noroxycodone and noroxymorphone decreased by 44% (p<0.001) and 45% (p<0.001), respectively. Oxymorphone AUC(0-∞) increased by 1.6-fold (p<0.01) after grapefruit juice, but the AUC(m)/AUC(p) remained unchanged. Pharmacodynamic changes were modest and only self-reported performance significantly impaired after grapefruit juice. Analgesic effects were not influenced. Grapefruit juice inhibited the CYP3A4-mediated first-pass metabolism of oxycodone, decreased the formation of noroxycodone and noroxymorphone and increased that of oxymorphone. We conclude that dietary consumption of grapefruit products may increase the concentrations and effects of oxycodone in clinical use.

St John's wort greatly reduces the concentrations of oral oxycodone.

BACKGROUND: Chronic pain is associated with depression. Self-treatment of depression with herbal over-the-counter medicine St John's wort makes pain patients prone to drug interactions. AIMS: The aim of this study was to assess the potential of St John's wort to alter the CYP3A-mediated metabolism of a mu-opioid receptor agonist, oxycodone. METHODS: The study design was placebo-controlled, randomized, cross-over with two phases at intervals of 4 weeks and was conducted with 12 healthy participants. St John's wort (Jarsin) or placebo was administered t.i.d. for 15 days and oral oxycodone hydrochloride 15 mg on day 14. Oxycodone pharmacokinetics and pharmacodynamics were compared after St John's wort or placebo. Behavioural and analgesic effects were assessed with subjective visual analogue scales and cold pressor test. Plasma drug concentrations were measured from 0 to 48 h, behavioural and analgesic effects from 0 to 12 h. RESULTS: Following St John's wort administration the oxycodone AUC decreased 50% (p<0.001). Oxycodone elimination half-life shortened from a mean+/-SD 3.8+/-0.7 to 3.0+/-0.4h (p<0.001). The self-reported drug effect of oxycodone as measured by AUEC(0-12) decreased significantly (p=0.004). Differences between St John's wort and placebo phases in cold pain threshold and intensity AUEC(0-12) were not observed. CONCLUSIONS: St John's wort greatly reduced the plasma concentrations of oral oxycodone. The self-reported drug effect of oxycodone decreased significantly. This interaction may potentially be of some clinical significance when treating patients with chronic pain.