Mari Fihlman1,2, Tuija Hemmilä2, Nora M Hagelberg1,2, Kristiina Kuusniemi1,2, Janne T Backman3, Jouko Laitila3, Kari Laine4,5, Pertti J Neuvonen3, Klaus T Olkkola6, Teijo I Saari7,8. 1. Department of Anaesthesiology and Intensive Care, University of Turku, P.O. Box 52, Kiinamyllynkatu 4-8, FI-20521, Turku, Finland. 2. Division of Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital, 20521, Turku, Finland. 3. Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, 00014, Helsinki, Finland. 4. Department of Pharmacology, Drug Development and Therapeutics, University of Turku, 20100, Turku, Finland. 5. Medbase Ltd, FI-20100, Turku, Finland. 6. Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, 00014, Helsinki, Finland. 7. Department of Anaesthesiology and Intensive Care, University of Turku, P.O. Box 52, Kiinamyllynkatu 4-8, FI-20521, Turku, Finland. teijo.saari@utu.fi. 8. Division of Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital, 20521, Turku, Finland. teijo.saari@utu.fi.
Abstract
PURPOSE: 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 (t ½ ) 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.
RCT Entities:
PURPOSE: 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 (t ½ ) 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: Sarah D McAleer; Richard J Mills; Torsten Polack; Tanweer Hussain; Paul E Rolan; Alan D Gibbs; Frank G P Mullins; Ziad Hussein Journal: Drug Alcohol Depend Date: 2003-10-24 Impact factor: 4.492
Authors: Ellen G J Hulskotte; R Douglas Bruce; Hwa-Ping Feng; Lynn R Webster; Feng Xuan; Wen H Lin; Edward O'Mara; John A Wagner; Joan R Butterton Journal: Eur J Clin Pharmacol Date: 2015-02-11 Impact factor: 2.953
Authors: Edward Michna; Edgar L Ross; Wilfred L Hynes; Srdjan S Nedeljkovic; Sharonah Soumekh; David Janfaza; Diane Palombi; Robert N Jamison Journal: J Pain Symptom Manage Date: 2004-09 Impact factor: 3.612
Authors: David E Moody; Matthew H Slawson; Eric C Strain; John D Laycock; Alan C Spanbauer; Rodger L Foltz Journal: Anal Biochem Date: 2002-07-01 Impact factor: 3.365
Authors: Mari Fihlman; Tuija Hemmilä; Nora M Hagelberg; Janne T Backman; Jouko Laitila; Kari Laine; Pertti J Neuvonen; Klaus T Olkkola; Teijo I Saari Journal: Eur J Clin Pharmacol Date: 2018-08-30 Impact factor: 2.953