Voriconazole greatly increases the exposure to oral buprenorphine
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.
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.
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.
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.
KeywordsBuprenorphine Norbuprenorphine Voriconazole Pharmacokinetics Drug-drug interaction CYP3A4 Transporters
We thank Mrs. Elina Kahra (medical laboratory technologist, Clinical Pharmacology, TYKSLAB, Hospital District of Southwest Finland, Turku, Finland) for her skillful technical assistance.
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.
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.
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