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Development of a Generic Fetal Physiologically Based Pharmacokinetic Model and Prediction of Human Maternal and Fetal Organ Concentrations of Cefuroxime

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Abstract

Background and Objective

Physiologically based pharmacokinetic (PBPK) models for pregnant women have recently been successfully used to predict maternal and umbilical cord pharmacokinetics (PK). Because there is very limited opportunity for conducting clinical and PK investigations for fetal drug exposure, PBPK models may provide further insights. The objectives of this study were to extend a whole-body pregnancy PBPK model by multiple compartments representing fetal organs, and to predict the PK of cefuroxime in the maternal and fetal plasma, the amniotic fluid, and several fetal organs.

Methods

To this end, a previously developed pregnancy PBPK model for cefuroxime was updated using the open-source software Open Systems Pharmacology (PK-Sim®/MoBi®). Multiple compartments were implemented to represent fetal organs including brain, heart, liver, lungs, kidneys, the gastrointestinal tract (GI), muscles, and fat tissue, as well as another compartment lumping organs and tissues not explicitly represented.

Results

This novel PBPK model successfully predicted cefuroxime concentrations in maternal blood, umbilical cord, amniotic fluid, and several fetal organs including heart, liver, and lungs. Further model validation with additional clinical PK data is needed to build confidence in the model.

Conclusions

Being developed with an open-source software, the presented generic model can be freely re-used and tailored to address specific questions at hand, e.g., to assist the design of clinical studies in the context of drug research or to predict fetal organ concentrations of chemicals in the context of fetal health risk assessment.

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Authors and Affiliations

  1. Division of Clinical Pharmacology, Children’s National Hospital, Washington, DC, USA

    Xiaomei I. Liu & John van den Anker

  2. Office of Pediatric Therapeutics, US Food and Drug Administration, Silver Spring, MD, USA

    Dionna J. Green

  3. Division of Maternal-Fetal Medicine, Department of OB/Gyn, George Washington University, Washington, DC, USA

    Homa K. Ahmadzia

  4. Office of Clinical Pharmacology, US Food and Drug Administration, Silver Spring, MD, USA

    Gilbert J. Burckart

  5. Bayer HealthCare SAS, Loos, France

    André Dallmann

  6. On Behalf of: Pharmacometrics/Modeling and Simulation, Research and Development, Pharmaceuticals, Bayer AG, Leverkusen, Germany

    André Dallmann

Authors
  1. Xiaomei I. Liu
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  3. John van den Anker
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  4. Homa K. Ahmadzia
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  6. André Dallmann
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Corresponding author

Correspondence to Xiaomei I. Liu.

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Funding

This work was supported by an FDA Perinatal Health Center Excellence grant (Dionna Green, PI).

Conflict of interest

Dr. André Dallmann is an employee of Bayer AG and uses Open Systems Pharmacology software, tools, and models in his professional role. The remaining authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethics approval

Not applicable.

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Not applicable.

Consent for publication

Not applicable.

Availability of data and material

The data are from the literature and are cited in the references.

Code availability

The PBPK model will be available on the OSP GitHub website and can be downloaded freely.

Author contributions

AD and XIL wrote the manuscript. AD, XIL DG, JVA, HA, and GB designed the research. AD and XIL performed the research. AD and XIL analyzed the data.

Additional information

Disclaimer

The views expressed in this paper are those of the authors and do not necessarily represent those of the FDA. No broader FDA policies or perspectives are intended nor should be inferred. The FDA does not recommend any specific PBPK software.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 781 KB)

Supplementary file2 (DOCX 17 KB)

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Liu, X.I., Green, D.J., van den Anker, J. et al. Development of a Generic Fetal Physiologically Based Pharmacokinetic Model and Prediction of Human Maternal and Fetal Organ Concentrations of Cefuroxime. Clin Pharmacokinet 63, 69–78 (2024). https://doi.org/10.1007/s40262-023-01323-6

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  • DOI: https://doi.org/10.1007/s40262-023-01323-6

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