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

Vanessa Zhu; Jürgen Burhenne; Johanna Weiss; Mathias Haag; Ute Hofmann; Matthias Schwab; Stephan Urban; Gerd Mikus; David Czock; Walter E Haefeli; Antje Blank

doi:10.3389/fphar.2023.1128547

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

Front Pharmacol. 2023 Apr 6:14:1128547. doi: 10.3389/fphar.2023.1128547. eCollection 2023.

Authors

Vanessa Zhu^{1

2}, Jürgen Burhenne^{1

2}, Johanna Weiss^{1

2}, Mathias Haag^{3

4}, Ute Hofmann^{3

4}, Matthias Schwab^{3

5

6}, Stephan Urban^{2

7}, Gerd Mikus^{1

2}, David Czock^{1

2}, Walter E Haefeli^{1

2}, Antje Blank^{1

2}

Affiliations

¹ Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Heidelberg, Germany.
² German Center for Infection Research (DZIF) Partner Site Heidelberg, Heidelberg University Hospital, Heidelberg, Germany.
³ Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
⁴ University of Tübingen, Tübingen, Germany.
⁵ Departments of Clinical Pharmacology and of Biochemistry and Pharmacy, University of Tübingen, Tübingen, Germany.
⁶ Cluster of Excellence iFIT (EXC2180), Image-guided and Functionally Instructed Tumor Therapies, University of Tübingen, Tübingen, Germany.
⁷ Department of Infectious Diseases, Molecular Virology, Heidelberg University Hospital, Heidelberg, Germany.

Abstract

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.

Keywords: NTCP; OATP1B; SLC10A1; SLCO1B; bulevirtide; drug-drug interaction (DDI); hepatitis D virus infection; myrcludex B.

Grants and funding

The legal sponsor of this trial was the Heidelberg University Medical Faculty. The trial was supported by the German Center for Infection Research (TI 02.001 DZIF-CTU). Myr GmbH (Bad Homburg, Germany), now legally followed by Gilead Sciences Inc. (Martinsried, Germany) provided the investigator’s brochure and the investigational medicinal product dossier. MH, UH, and MS were in part supported by the Robert Bosch Stiftung Stuttgart, Germany. This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy—EXC 2180—390900677. SU received funding from the German Centre of Infectious Diseases (DZIF).