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European Journal of Clinical Pharmacology

, Volume 74, Issue 12, pp 1615–1622 | Cite as

Voriconazole greatly increases the exposure to oral buprenorphine

  • Mari Fihlman
  • Tuija Hemmilä
  • Nora M. Hagelberg
  • Janne T. Backman
  • Jouko Laitila
  • Kari Laine
  • Pertti J Neuvonen
  • Klaus T. Olkkola
  • Teijo I. Saari
Pharmacokinetics and Disposition

Abstract

Purpose

Buprenorphine has low oral bioavailability. Regardless of sublingual administration, a notable part of buprenorphine is exposed to extensive first-pass metabolism by the cytochrome P450 (CYP) 3A4. As drug interaction studies with buprenorphine are limited, we wanted to investigate the effect of voriconazole, a strong CYP3A4 inhibitor, on the pharmacokinetics and pharmacodynamics of oral buprenorphine.

Methods

Twelve healthy volunteers were given either placebo or voriconazole (orally, 400 mg twice on day 1 and 200 mg twice on days 2–5) for 5 days in a randomized, cross-over study. On day 5, they ingested 0.2 mg (3.6 mg during placebo phase) oral buprenorphine. We measured plasma and urine concentrations of buprenorphine and norbuprenorphine and monitored their pharmacological effects. Pharmacokinetic parameters were normalized for a buprenorphine dose of 1.0 mg.

Results

Voriconazole greatly increased the mean area under the plasma concentration–time curve (AUC0–18) of buprenorphine (4.3-fold, P < 0.001), its peak concentration (Cmax) (3.9-fold), half-life (P < 0.05), and excretion into urine (Ae; P < 0.001). Voriconazole also markedly enhanced the Cmax (P < 0.001), AUC0–18 (P < 0.001), and Ae (P < 0.05) of unconjugated norbuprenorphine but decreased its renal clearance (P < 0.001). Mild dizziness and nausea occurred during both study phases.

Conclusions

Voriconazole greatly increases exposure to oral buprenorphine, mainly by inhibiting intestinal and liver CYP3A4. Effect on some transporters may explain elevated norbuprenorphine concentrations. Although oral buprenorphine is not commonly used, this interaction may become relevant in patients receiving sublingual buprenorphine together with voriconazole or other CYP3A4 or transporter inhibitors.

Keywords

Buprenorphine Norbuprenorphine Voriconazole Pharmacokinetics Drug-drug interaction CYP3A4 Transporters 

Notes

Acknowledgements

We thank Mrs. Elina Kahra (medical laboratory technologist, Clinical Pharmacology, TYKSLAB, Hospital District of Southwest Finland, Turku, Finland) for her skillful technical assistance.

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 and manuscript preparation. Tuija Hemmilä participated the clinical phase and data collection. Janne T. Backman, Jouko Laitila, and Pertti J Neuvonen performed the analytical assays and participated in manuscript preparation. Teijo Saari 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.

Funding information

This study was supported financially by Turku University Hospital research fund (EVO 13821), Turku, Finland.

Compliance with ethical standards

The study protocol was approved by the ethics committee of the Hospital District of Southwest Finland and by the Finnish National Agency for Medicines and was registered in the EudraCT clinical trials register under code 2011-001939-23.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

228_2018_2548_Fig2_ESM.png (137 kb)
Supplemental Figure 1.

Individual pharmacokinetic parameters after oral buprenorphine. Values for maximum concentration (Cmax), area under plasma concentration–time curve (AUC0-18), elimination half-life (t½) and amount of urinary buprenorphine excreted during 18 h (Ae (0-18)) in 12 healthy subjects after 3.6 mg (placebo phase) or 0.2 mg (voriconazole phase) of oral buprenorphine on the fifth day of pretreatment with placebo or voriconazole 400 mg twice on day 1 and 200 mg twice on days 2-5. The horizontal line in the box represents the median, white diamonds show the mean, the box shows the interquartile range, and whiskers show the 10th and 90th percentiles. Values are normalized for an oral dose of 1.0 mg. (PNG 137 kb)

228_2018_2548_MOESM1_ESM.tiff (140 kb)
High resolution image (TIFF 139 kb)
228_2018_2548_Fig3_ESM.png (8.9 mb)
Supplemental Figure 2.

Individual pharmacokinetic parameters of norbuprenorphine after oral buprenorphine. Values for maximum concentration (Cmax), area under plasma concentration–time curve (AUC0-18), amount of urinary norbuprenorphine excreted during 18 h (Ae(0-18)) and renal clearance (Clrenal) in 12 healthy subjects after 3.6 mg (placebo phase) or 0.2 mg (voriconazole phase) of oral buprenorphine on the fifth day of pretreatment with placebo or voriconazole 400 mg twice on day 1 and 200 mg twice on days 2-5. The horizontal line in the box represents the median, white diamonds show the mean, the box shows the interquartile range, and whiskers show the 10th and 90th percentiles. Values are normalized for an oral dose of 1.0 mg. (PNG 9110 kb)

228_2018_2548_MOESM2_ESM.tiff (978 kb)
High resolution image (TIFF 978 kb)
228_2018_2548_MOESM3_ESM.pdf (96 kb)
ESM 3 (PDF 95 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Mari Fihlman
    • 1
    • 2
  • Tuija Hemmilä
    • 2
  • Nora M. Hagelberg
    • 1
    • 2
  • Janne T. Backman
    • 3
  • Jouko Laitila
    • 3
  • Kari Laine
    • 4
    • 5
  • Pertti J Neuvonen
    • 3
  • Klaus T. Olkkola
    • 6
  • Teijo I. Saari
    • 1
    • 2
  1. 1.Department of Anaesthesiology and Intensive CareUniversity of TurkuTurkuFinland
  2. 2.Division of Perioperative Services, Intensive Care and Pain MedicineTurku University HospitalTurkuFinland
  3. 3.Department of Clinical PharmacologyUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland
  4. 4.Department of Pharmacology, Drug Development and TherapeuticsUniversity of TurkuTurkuFinland
  5. 5.Medbase Ltd.TurkuFinland
  6. 6.Department of Anaesthesiology, Intensive Care and Pain MedicineUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland

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