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Evaluation of the drug-drug interaction potential of the novel hepatitis B and D virus entry inhibitor bulevirtide at OATP1B in healthy volunteers

Introduction: Bulevirtide is a first-in-class antiviral drug to treat chronic hepatitis B/D. We investigated the drug-drug interaction potential and pharmacokinetics of high-dose subcutaneous bulevirtide (5 mg twice daily) with organic anion transporting polypeptide 1B1 (OATP1B1) and cytochrome P450...

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Autores principales: Zhu, Vanessa, Burhenne, Jürgen, Weiss, Johanna, Haag, Mathias, Hofmann, Ute, Schwab, Matthias, Urban, Stephan, Mikus, Gerd, Czock, David, Haefeli, Walter E., Blank, Antje
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10117888/
https://www.ncbi.nlm.nih.gov/pubmed/37089922
http://dx.doi.org/10.3389/fphar.2023.1128547
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author Zhu, Vanessa
Burhenne, Jürgen
Weiss, Johanna
Haag, Mathias
Hofmann, Ute
Schwab, Matthias
Urban, Stephan
Mikus, Gerd
Czock, David
Haefeli, Walter E.
Blank, Antje
author_facet Zhu, Vanessa
Burhenne, Jürgen
Weiss, Johanna
Haag, Mathias
Hofmann, Ute
Schwab, Matthias
Urban, Stephan
Mikus, Gerd
Czock, David
Haefeli, Walter E.
Blank, Antje
author_sort Zhu, Vanessa
collection PubMed
description Introduction: Bulevirtide is a first-in-class antiviral drug to treat chronic hepatitis B/D. We investigated the drug-drug interaction potential and pharmacokinetics of high-dose subcutaneous bulevirtide (5 mg twice daily) with organic anion transporting polypeptide 1B1 (OATP1B1) and cytochrome P450 (CYP) 3A4. Methods: This was a single-center, open-label, fixed-sequence drug-drug interaction trial in 19 healthy volunteers. Before and at bulevirtide steady state, participants ingested a single 40 mg dose of pravastatin. A midazolam microdose was applied to quantify CYP3A4 activity. Results: At bulevirtide steady state, pravastatin area under the concentration-time curve (AUC(0–∞)) increased 1.32-fold (90% CI 1.08-1.61). The 5 mg bulevirtide twice-daily treatment resulted in a mean AUC(0-12) of 1210 h*ng/ml (95% CI 1040-1408) and remained essentially unchanged under the influence of pravastatin. CYP3A4 activity did not change to a clinically relevant extent. As expected, total bile acids increased substantially (35-fold) compared to baseline during bulevirtide treatment. All study medication was well tolerated. Discussion: The study demonstrated that high-dose bulevirtide inhibited OATP1B-mediated hepatic uptake of the marker substrate pravastatin but the extent is considered clinically not relevant. Changes in CYP3A4 activity were also not clinically relevant. In conclusion, this study suggests that OATP1B substrate drugs as well as CYP3A4 substrates may safely be used without dose adjustment in patients treated with bulevirtide. However, in patients using high statin doses and where concomitant factors potentially further increase statin exposure, caution may be required when using bulevirtide.
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spelling pubmed-101178882023-04-21 Evaluation of the drug-drug interaction potential of the novel hepatitis B and D virus entry inhibitor bulevirtide at OATP1B in healthy volunteers Zhu, Vanessa Burhenne, Jürgen Weiss, Johanna Haag, Mathias Hofmann, Ute Schwab, Matthias Urban, Stephan Mikus, Gerd Czock, David Haefeli, Walter E. Blank, Antje Front Pharmacol Pharmacology Introduction: Bulevirtide is a first-in-class antiviral drug to treat chronic hepatitis B/D. We investigated the drug-drug interaction potential and pharmacokinetics of high-dose subcutaneous bulevirtide (5 mg twice daily) with organic anion transporting polypeptide 1B1 (OATP1B1) and cytochrome P450 (CYP) 3A4. Methods: This was a single-center, open-label, fixed-sequence drug-drug interaction trial in 19 healthy volunteers. Before and at bulevirtide steady state, participants ingested a single 40 mg dose of pravastatin. A midazolam microdose was applied to quantify CYP3A4 activity. Results: At bulevirtide steady state, pravastatin area under the concentration-time curve (AUC(0–∞)) increased 1.32-fold (90% CI 1.08-1.61). The 5 mg bulevirtide twice-daily treatment resulted in a mean AUC(0-12) of 1210 h*ng/ml (95% CI 1040-1408) and remained essentially unchanged under the influence of pravastatin. CYP3A4 activity did not change to a clinically relevant extent. As expected, total bile acids increased substantially (35-fold) compared to baseline during bulevirtide treatment. All study medication was well tolerated. Discussion: The study demonstrated that high-dose bulevirtide inhibited OATP1B-mediated hepatic uptake of the marker substrate pravastatin but the extent is considered clinically not relevant. Changes in CYP3A4 activity were also not clinically relevant. In conclusion, this study suggests that OATP1B substrate drugs as well as CYP3A4 substrates may safely be used without dose adjustment in patients treated with bulevirtide. However, in patients using high statin doses and where concomitant factors potentially further increase statin exposure, caution may be required when using bulevirtide. Frontiers Media S.A. 2023-04-06 /pmc/articles/PMC10117888/ /pubmed/37089922 http://dx.doi.org/10.3389/fphar.2023.1128547 Text en Copyright © 2023 Zhu, Burhenne, Weiss, Haag, Hofmann, Schwab, Urban, Mikus, Czock, Haefeli and Blank. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Zhu, Vanessa
Burhenne, Jürgen
Weiss, Johanna
Haag, Mathias
Hofmann, Ute
Schwab, Matthias
Urban, Stephan
Mikus, Gerd
Czock, David
Haefeli, Walter E.
Blank, Antje
Evaluation of the drug-drug interaction potential of the novel hepatitis B and D virus entry inhibitor bulevirtide at OATP1B in healthy volunteers
title Evaluation of the drug-drug interaction potential of the novel hepatitis B and D virus entry inhibitor bulevirtide at OATP1B in healthy volunteers
title_full Evaluation of the drug-drug interaction potential of the novel hepatitis B and D virus entry inhibitor bulevirtide at OATP1B in healthy volunteers
title_fullStr Evaluation of the drug-drug interaction potential of the novel hepatitis B and D virus entry inhibitor bulevirtide at OATP1B in healthy volunteers
title_full_unstemmed Evaluation of the drug-drug interaction potential of the novel hepatitis B and D virus entry inhibitor bulevirtide at OATP1B in healthy volunteers
title_short Evaluation of the drug-drug interaction potential of the novel hepatitis B and D virus entry inhibitor bulevirtide at OATP1B in healthy volunteers
title_sort evaluation of the drug-drug interaction potential of the novel hepatitis b and d virus entry inhibitor bulevirtide at oatp1b in healthy volunteers
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10117888/
https://www.ncbi.nlm.nih.gov/pubmed/37089922
http://dx.doi.org/10.3389/fphar.2023.1128547
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