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Voriconazole more likely than posaconazole increases plasma exposure to sublingual buprenorphine causing a risk of a clinically important interaction

  • Pharmacokinetics and Disposition
  • Published:
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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.

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Acknowledgments

We thank Mrs. Elina Kahra (medical laboratory technologist, Clinical Pharmacology, TYKSLAB, Hospital District of Southwest Finland, Turku, Finland) for her skillful technical assistance. This study was supported financially by Turku University Hospital research fund (EVO 13821), Turku, Finland.

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Authors and Affiliations

  1. Department of Anaesthesiology and Intensive Care, University of Turku, P.O. Box 52, Kiinamyllynkatu 4-8, FI-20521, Turku, Finland

    Mari Fihlman, Nora M. Hagelberg, Kristiina Kuusniemi & Teijo I. Saari

  2. Division of Perioperative Services, Intensive Care Medicine and Pain Management, Turku University Hospital, 20521, Turku, Finland

    Mari Fihlman, Tuija Hemmilä, Nora M. Hagelberg, Kristiina Kuusniemi & Teijo I. Saari

  3. Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, 00014, Helsinki, Finland

    Janne T. Backman, Jouko Laitila & Pertti J. Neuvonen

  4. Department of Pharmacology, Drug Development and Therapeutics, University of Turku, 20100, Turku, Finland

    Kari Laine

  5. Medbase Ltd, FI-20100, Turku, Finland

    Kari Laine

  6. Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Helsinki and Helsinki University Hospital, 00014, Helsinki, Finland

    Klaus T. Olkkola

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  1. Mari Fihlman
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  2. Tuija Hemmilä
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Correspondence to Teijo I. Saari.

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Authors’ contributions

Mari Fihlman took care of the clinical phase of the study and data collection, participated in data analysis and statistical analysis and wrote the manuscript. Klaus Olkkola and Kari Laine designed the study, wrote the protocol, supervised and coordinated the clinical implementation of the study, and participated in data analysis. Tuija Hemmilä and Kristiina Kuusniemi participated the clinical phase and data collection. Janne T. Backman, Jouko Laitila and Pertti J Neuvonen performed the analytical assays. Teijo Saari designed the study, analyzed the data, performed statistical analysis, and wrote the manuscript. All authors materially participated in the research and/or manuscript preparation. All authors have contributed to and approved the final manuscript.

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The authors declare that they have no conflict of interest.

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Fihlman, M., Hemmilä, T., Hagelberg, N.M. et al. Voriconazole more likely than posaconazole increases plasma exposure to sublingual buprenorphine causing a risk of a clinically important interaction. Eur J Clin Pharmacol 72, 1363–1371 (2016). https://doi.org/10.1007/s00228-016-2109-y

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