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A physiologically based pharmacokinetic (PBPK) parent-metabolite model of the chemotherapeutic zoptarelin doxorubicin—integration of in vitro results, Phase I and Phase II data and model application for drug–drug interaction potential analysis

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Abstract

Purpose

Zoptarelin doxorubicin is a fusion molecule of the chemotherapeutic doxorubicin and a luteinizing hormone-releasing hormone receptor (LHRHR) agonist, designed for drug targeting to LHRHR positive tumors. The aim of this study was to establish a physiologically based pharmacokinetic (PBPK) parent-metabolite model of zoptarelin doxorubicin and to apply it for drug–drug interaction (DDI) potential analysis.

Methods

The PBPK model was built in a two-step procedure. First, a model for doxorubicin was developed, using clinical data of a doxorubicin study arm. Second, a parent-metabolite model for zoptarelin doxorubicin was built, using clinical data of three different zoptarelin doxorubicin studies with a dosing range of 10–267 mg/m2, integrating the established doxorubicin model. DDI parameters determined in vitro were implemented to predict the impact of zoptarelin doxorubicin on possible victim drugs.

Results

In vitro, zoptarelin doxorubicin inhibits the drug transporters organic anion-transporting polypeptide 1B3 (OATP1B3) and organic cation transporter 2 (OCT2). The model was applied to evaluate the in vivo inhibition of these transporters in a generic manner, predicting worst-case scenario decreases of 0.5% for OATP1B3 and of 2.5% for OCT2 transport rates. Specific DDI simulations using PBPK models of simvastatin (OATP1B3 substrate) and metformin (OCT2 substrate) predict no significant changes of the plasma concentrations of these two victim drugs during co-administration.

Conclusions

The first whole-body PBPK model of zoptarelin doxorubicin and its active metabolite doxorubicin has been successfully established. Zoptarelin doxorubicin shows no potential for DDIs via OATP1B3 and OCT2.

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Acknowledgements

The authors gratefully acknowledge the patients that participated in the clinical studies and the medical staff involved in patient care and study execution.

Author information

Authors and Affiliations

  1. Clinical Pharmacy, Saarland University, Campus C2 2, 66123, Saarbruecken, Germany

    Nina Hanke, Daniel Moj, Jan-Georg Wojtyniak, Hannah Britz & Thorsten Lehr

  2. Aeterna Zentaris GmbH, Weismuellerstr. 50, 60314, Frankfurt, Germany

    Michael Teifel, Babette Aicher, Herbert Sindermann & Nicola Ammer

Authors
  1. Nina Hanke
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  2. Michael Teifel
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  3. Daniel Moj
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  4. Jan-Georg Wojtyniak
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  6. Babette Aicher
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  7. Herbert Sindermann
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  9. Thorsten Lehr
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Corresponding author

Correspondence to Thorsten Lehr.

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Funding

This study was funded by Aeterna Zentaris.

Conflict of interest

Nina Hanke, Daniel Moj, Jan-Georg Wojtyniak and Hannah Britz declare that they have no conflict of interest. Michael Teifel, Babette Aicher, Herbert Sindermann and Nicola Ammer are employees of Aeterna Zentaris. Thorsten Lehr has received research grants from Aeterna Zentaris.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

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Informed consent was obtained from all individual participants included in the study.

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Hanke, N., Teifel, M., Moj, D. et al. A physiologically based pharmacokinetic (PBPK) parent-metabolite model of the chemotherapeutic zoptarelin doxorubicin—integration of in vitro results, Phase I and Phase II data and model application for drug–drug interaction potential analysis. Cancer Chemother Pharmacol 81, 291–304 (2018). https://doi.org/10.1007/s00280-017-3495-2

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  • DOI: https://doi.org/10.1007/s00280-017-3495-2

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