title: Oxycodone concentrations are greatly increased by the concomitant use of ritonavir or lopinavir/ritonavir.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine, Turku University Hospital and University of Turku, P.O. Box 52, Kiinamyllynkatu 4-8, 20521 Turku, Finland. tuija.nieminen@utu.fi
authors.forename: Tuija H
authors.initials: TH
authors.lastname: Nieminen
authors.forename: Nora M
authors.initials: NM
authors.lastname: Hagelberg
authors.forename: Teijo I
authors.initials: TI
authors.lastname: Saari
authors.forename: Mikko
authors.initials: M
authors.lastname: Neuvonen
authors.forename: Pertti J
authors.initials: PJ
authors.lastname: Neuvonen
authors.forename: Kari
authors.initials: K
authors.lastname: Laine
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Olkkola
mesh_terms: D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D005387:Finland; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D016014:Linear Models; D061466:Lopinavir; D008297:Male; D010098:Oxycodone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D010146:Pain / Q000150:complications / Q000188:drug therapy; D011744:Pyrimidinones / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D012016:Reference Values; D019438:Ritonavir / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D013997:Time Factors; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir; D010098:Oxycodone; D019438:Ritonavir