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Evaluation of Various Approaches to Estimate Transplacental Clearance of Vancomycin for Predicting Fetal Concentrations using a Maternal–Fetal Physiologically Based Pharmacokinetic Model

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Abstract

Background

Evaluating drug transplacental clearance is vital for forecasting fetal drug exposure. Ex vivo human placenta perfusion experiments are the most suitable approach for this assessment. Various in silico methods are also proposed. This study aims to compare these prediction methods for drug transplacental clearance, focusing on the large molecular weight drug vancomycin (1449.3 g/mol), using maternal–fetal physiologically based pharmacokinetic (m-f PBPK) modeling.

Methods

Ex vivo human placenta perfusion experiments, in silico approaches using intestinal permeability as a substitute (quantitative structure property relationship (QSPR) model and Caco-2 permeability in vitro-in vivo correlation model) and midazolam calibration model with Caco-2 scaling were assessed for determining the transplacental clearance (CLPD) of vancomycin. The m-f PBPK model was developed stepwise using Simcyp, incorporating the determined CLPD values as a crucial input parameter for transplacental kinetics.

Results

The developed PBPK model of vancomycin for non-pregnant adults demonstrated excellent predictive performance. By incorporating the CLPD parameterization derived from ex vivo human placenta perfusion experiments, the extrapolated m-f PBPK model consistently predicted maternal and fetal concentrations of vancomycin across diverse doses and distinct gestational ages. However, when the CLPD parameter was derived from alternative prediction methods, none of the extrapolated maternal–fetal PBPK models produced fetal predictions in line with the observed data.

Conclusion

Our study showcased that combination of ex vivo human placenta perfusion experiments and m-f PBPK model has the capability to predict fetal exposure for the large molecular weight drug vancomycin, whereas other in silico approaches failed to achieve the same level of accuracy.

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Data Availability

The data that support the findings of this study are available on request from the corresponding author.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant number: 82104306), the Science and Technology Innovation Program of Hunan Province (grant number: 2022RC1229), and the Fundamental Research Funds for the Central Universities of Central South University (grant number: 2024ZZTS0986). Certara UK Limited (Simcyp Division) granted access to the Simcyp Simulators through a sponsored academic licence (subject to conditions).

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Author notes

  1. Yunan Yan and Qiushi Wang contributed equally to this work.

Authors and Affiliations

  1. Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Tongzipo Road 172, Changsha, 410013, China

    Yunan Yan, Qiushi Wang & Feifan Xie

  2. The Affiliated Changsha Hospital of Xiangya School of Medicine, Central South University, Changsha, China

    Wei Wu

  3. Department of Pharmacy, The First Hospital of Changsha, Changsha, China

    Wei Wu

  4. Department of Pathology, School of Basic Medical Science, Central South University, Changsha, China

    Hanxi Yi

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Contributions

Yunan Yan and Qiushi Wang developed the PBPK model and write the manuscript. Wei Wu and Hanxi Yi reviewed the manuscript. Feifan Xie conceived the study idea, reviewed, and approved the final manuscript version.

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Correspondence to Feifan Xie.

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Yan, Y., Wang, Q., Wu, W. et al. Evaluation of Various Approaches to Estimate Transplacental Clearance of Vancomycin for Predicting Fetal Concentrations using a Maternal–Fetal Physiologically Based Pharmacokinetic Model. Pharm Res (2024). https://doi.org/10.1007/s11095-024-03705-2

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