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

• Published in: European journal of clinical pharmacology Vol. 66; no. 10; pp. 977 - 985
• Main Authors: Nieminen, Tuija H, Hagelberg, Nora M, 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 01.10.2010; Springer-Verlag; Springer; Springer Nature B.V; Springer Verlag
• Subjects: Adult; Analgesics, Opioid - administration & dosage; Analgesics, Opioid - blood; Analgesics, Opioid - pharmacokinetics; Analgesics, Opioid - pharmacology; Antiviral drugs; Area Under Curve; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Clinical Trial; Cross-Over Studies; Drug Administration Schedule; Drug Interactions; Drug therapy; Drug Therapy, Combination; Female; Finland; HIV Infections - complications; HIV Infections - drug therapy; HIV Protease Inhibitors - administration & dosage; HIV Protease Inhibitors - adverse effects; HIV Protease Inhibitors - pharmacology; Humans; Interaction; Kinetics; Linear Models; Lopinavir; Lopinavir/ritonavir; Male; Medical sciences; Oxycodone; Oxycodone - administration & dosage; Oxycodone - blood; Oxycodone - pharmacokinetics; Oxycodone - pharmacology; Pain - complications; Pain - drug therapy; pharmacokinetics; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pyrimidinones - administration & dosage; Pyrimidinones - adverse effects; Pyrimidinones - pharmacology; Reference Values; Ritonavir; Ritonavir - administration & dosage; Ritonavir - adverse effects; Ritonavir - pharmacology; Time Factors; Young Adult; Finland; Pharmacodynamics; Lopinavir/ritonavir; Pharmacokinetics; Ritonavir; Oxycodone; Interaction; Human; Antiretroviral agent; Enzyme; Lopinavir; Enzyme inhibitor; Opiates; Narcotic analgesic; Biological activity; Peptidases; Hydrolases; Antiviral; Protease inhibitor
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-010-0879-1

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.