Voriconazole drastically increases exposure to oral oxycodone

Hagelberg, Nora; Nieminen, Tuija H.; Saari, Teijo I.; Neuvonen, Mikko; Neuvonen, Pertti J.; Laine, Kari; Olkkola, Klaus T.

doi:10.1007/s00228-008-0568-5

Cited by 74 publications

(51 citation statements)

References 47 publications

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“…In the present study ritonavir caused a 3-fold mean increase of oxycodone AUC 0-∞ , which is somewhat smaller than that observed after the azole antimycotic voriconazole (3.6-fold increase in oxycodone AUC 0-∞ ), but bigger than that observed for itrazonazole (2.4-fold increase) and telithromycin (1.8-fold increase) [25][26][27]. It can be speculated, although it seems doubtful, that the interaction between oxycodone and ritonavir would have been stronger, if a larger ritonavir dose would have been used as recommended by the manufacturer.…”

Section: Discussioncontrasting

confidence: 83%

“…In previous studies it has been shown, that CYP3A inhibitors voriconazole [25], itraconazole [26] and telithromycin [27] increased the concentrations of oxycodone and oxymorphone, but only minor changes have been observed in the pharmacological action of oxycodone following single doses in healthy volunteers. As HIV patients are often affected with moderate to severe pain, there is an obvious need for the concomitant use of antivirals and strong opioids, such as oxycodone.…”

Section: Discussionmentioning

confidence: 94%

“…In view of our previous studies, it was calculated, that 10 subjects would be required to detect a 30% difference in the area under the oxycodone concentration-time curves (AUC 0-∞ ) at a level of significance P = 0.05 and power of 80% [25][26][27]. To allow a drop-out rate of 20%, we decided to recruit 12 subjects.…”

Section: Participantsmentioning

confidence: 99%

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

Nieminen

Hagelberg

Saari

et al. 2010

Eur J Clin Pharmacol

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To cite this version:Methods: A randomized crossover study design with 3 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. Behavioural 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-(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 prolonged 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.

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Section: Discussioncontrasting

confidence: 83%

Section: Discussionmentioning

confidence: 94%

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

Nieminen

Hagelberg

Saari

et al. 2010

Eur J Clin Pharmacol

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“…Recent studies in healthy subjects show that in the elimination of oxycodone, CYP3A is more significant than CYP2D6. Inhibition of hepatic and/or intestinal CYP3A with voriconazole, itraconazole, ketoconazole, HIV protease inhibitors or grapefruit juice increases exposure to oral oxycodone in healthy subjects and may enhance its analgesic or adverse effects [1][2][3][4][5][6][7][8].…”

mentioning

confidence: 99%

“…inhibitors [1,5,6]. It is thus theoretically possible that one or both of these patients were ultrarapid metabolisers of CYP2D6.…”

mentioning

confidence: 99%

Interaction of oxycodone and voriconazole—a case series of patients with cancer pain supports the findings of randomised controlled studies with healthy subjects

Hagelberg

Nieminen

Saari

et al. 2011

Eur J Clin Pharmacol

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Physiologically based pharmacokinetic modelling of oxycodone drug–drug interactions

Rytkönen

Ranta

Kokki

et al. 2020

Biopharm & Drug Disp

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Oxycodone is an opioid analgesic with several pharmacologically active metabolites and relatively narrow therapeutic index. Cytochrome P450 (CYP) 3A4 and CYP2D6 play major roles in the metabolism of oxycodone and its metabolites. Thus, inhibition and induction of these enzymes may result in substantial changes in the exposure of both oxycodone and its metabolites. In this study, a physiologically based pharmacokinetic (PBPK) model was built using GastroPlus™ software for oxycodone, two primary metabolites (noroxycodone, oxymorphone) and one secondary metabolite (noroxymorphone). The model was built based on literature and in house in vitro and in silico data. The model was refined and verified against literature clinical data after oxycodone administration in the absence of drug-drug interactions (DDI). The model was further challenged with simulations of oxycodone DDI with CYP3A4 inhibitors ketoconazole and itraconazole, CYP3A4 inducer rifampicin and CYP2D6 inhibitor quinidine. The magnitude of DDI (AUC ratio) was predicted within 1.5-fold error for oxycodone, within 1.8-fold and 1.3-4.5-fold error for the primary metabolites noroxycodone and oxymorphone, respectively, and within 1.4-4.5-fold error for the secondary metabolite noroxymorphone, when compared to the mean observed AUC ratios. This work demonstrated the capability of PBPK model to simulate DDI of the administered compounds and the formed metabolites of both DDI victim and perpetrator. However, the predictions for the formed metabolites tend to be associated with higher uncertainty than the predictions for the administered compound. The oxycodone model provides a tool for forecasting oxycodone DDI with other CYP3A4 and CYP2D6 DDI perpetrators that may be coadministered with oxycodone.

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Voriconazole drastically increases exposure to oral oxycodone

Cited by 74 publications

References 47 publications

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

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

Interaction of oxycodone and voriconazole—a case series of patients with cancer pain supports the findings of randomised controlled studies with healthy subjects

Physiologically based pharmacokinetic modelling of oxycodone drug–drug interactions

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