title: Voriconazole more likely than posaconazole increases plasma exposure to sublingual buprenorphine causing a risk of a clinically important interaction.
abstract: OBJECTIVE
  This study aimed to determine possible effects of voriconazole and posaconazole on the pharmacokinetics and pharmacological effects of sublingual buprenorphine.
  
  
  METHODS
  We used a randomized, placebo-controlled crossover study design with 12 healthy male volunteers. Subjects were given a dose of 0.4 mg (0.6 mg during placebo phase) sublingual buprenorphine after a 5-day oral pretreatment with either (i) placebo, (ii) voriconazole 400 mg twice daily on the first day and 200 mg twice daily thereafter or (iii) posaconazole 400 mg twice daily. Plasma and urine concentrations of buprenorphine and its primary active metabolite norbuprenorphine were monitored over 18 h and pharmacological effects were measured.
  
  
  RESULTS
  Compared to placebo, voriconazole increased the mean area under the plasma concentration-time curve (AUC0-∞) of buprenorphine 1.80-fold (90 % confidence interval 1.45-2.24; P < 0.001), its peak concentration (Cmax) 1.37-fold (P < 0.013) and half-life (t½) 1.37-fold (P < 0.001). Posaconazole increased the AUC00-∞of buprenorphine 1.25-fold (P < 0.001). Most of the plasma norbuprenorphine concentrations were below the limit of quantification (0.05 ng/ml). Voriconazole, unlike posaconazole, increased the urinary excretion of norbuprenorphine 1.58-fold (90 % confidence interval 1.18-2.12; P < 0.001) but there was no quantifiable parent buprenorphine in urine. Plasma buprenorphine concentrations correlated with the pharmacological effects, but the effects did not differ significantly between the phases.
  
  
  CONCLUSIONS
  Voriconazole, and to a minor extent posaconazole, increase plasma exposure to sublingual buprenorphine, probably via inhibition of cytochrome P450 3 A and/or P-glycoprotein. Care should be exercised in the combined use of buprenorphine with triazole antimycotics, particularly with voriconazole, because their interaction can be of clinical importance.
authors: Department of Anaesthesiology and Intensive Care, University of Turku, P.O. Box 52, Kiinamyllynkatu 4-8, FI-20521, Turku, Finland.|Division of Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital, 20521, Turku, Finland.
authors: Mari
authors: M
authors: Fihlman
authors: Division of Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital, 20521, Turku, Finland.
authors: Tuija
authors: T
authors: Hemmilä
authors: Department of Anaesthesiology and Intensive Care, University of Turku, P.O. Box 52, Kiinamyllynkatu 4-8, FI-20521, Turku, Finland.|Division of Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital, 20521, Turku, Finland.
authors: Nora M
authors: NM
authors: Hagelberg
authors: Department of Anaesthesiology and Intensive Care, University of Turku, P.O. Box 52, Kiinamyllynkatu 4-8, FI-20521, Turku, Finland.|Division of Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital, 20521, Turku, Finland.
authors: Kristiina
authors: K
authors: Kuusniemi
authors: Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, 00014, Helsinki, Finland.
authors: Janne T
authors: JT
authors: Backman
authors: Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, 00014, Helsinki, Finland.
authors: Jouko
authors: J
authors: Laitila
authors: Department of Pharmacology, Drug Development and Therapeutics, University of Turku, 20100, Turku, Finland.|Medbase Ltd, FI-20100, Turku, Finland.
authors: Kari
authors: K
authors: Laine
authors: Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, 00014, Helsinki, Finland.
authors: Pertti J
authors: PJ
authors: Neuvonen
authors: Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, 00014, Helsinki, Finland.
authors: Klaus T
authors: KT
authors: Olkkola
authors: Department of Anaesthesiology and Intensive Care, University of Turku, P.O. Box 52, Kiinamyllynkatu 4-8, FI-20521, Turku, Finland. teijo.saari@utu.fi.|Division of Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital, 20521, Turku, Finland. teijo.saari@utu.fi.
authors: Teijo I
authors: TI
authors: Saari
mesh_terms: D000286:Administration, Sublingual; D000328:Adult; D000701:Analgesics, Opioid / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology*; D002047:Buprenorphine / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D018592:Cross-Over Studies; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D010146:Pain / Q000188:drug therapy; D016037:Single-Blind Method; D014230:Triazoles / Q000494:pharmacology*; D065819:Voriconazole / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; D000935:Antifungal Agents; D014230:Triazoles; D002047:Buprenorphine; C101425:posaconazole; D003577:Cytochrome P-450 Enzyme System; D065819:Voriconazole
keywords: Azole antifungals; Buprenorphine; Drug-drug interaction; Pharmacokinetics; Posaconazole; Voriconazole