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Fetal Physiologically Based Pharmacokinetic Models: Systems Information on Fetal Blood Components and Binding Proteins

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Abstract

Background

Fetal blood and plasma volume and binding components are critical parameters in a fetal physiologically based pharmacokinetic model. To date, a comprehensive review of their changes during fetal development has not been reported.

Objective

The objective of this work was to collate and analyze physiological information on fetal blood and plasma volume and binding component data during development and to provide a mathematical description of these parameters that can be integrated within a fetal physiologically based pharmacokinetic model.

Methods

A comprehensive literature search was conducted on fetal blood and plasma volume and binding component parameters and their changes during growth from apparently healthy fetuses from uncomplicated pregnancies. Collated data were assessed, integrated, and analyzed to establish continuous mathematical functions describing their growth trends with fetal age and weight.

Results

Data were available from 14 studies for blood, ten studies for hematocrit, 12 studies for albumin, and four studies for alpha-1-acid glycoprotein, while plasma and red blood cell volumes were described based on blood and hematocrit data. Fetal physiologically based pharmacokinetic parameters, including blood, plasma and red blood cell volumes, hematocrit, serum albumin, and acid glycoprotein were quantified as a function of fetal age and weight. Variability around the mean parameters at different fetal ages was also investigated. The growth of each of these parameters was different (with respect to direction and monotonicity).

Conclusions

Despite the limitations identified in the availability of some values, the collected data presented in this article provide a useful resource for fetal physiologically based pharmacokinetic modeling. Potential applications include predicting xenobiotic exposure and risk assessment in the fetus following maternally administered drugs or unintended exposure to environmental toxicants.

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Acknowledgements

We thank Ms. Eleanor Savill and Ms. Jessica Waite for their assistance with collecting the references and preparing the manuscript and Ruth Clayton for her helpful comments and proofreading.

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  1. Certara UK Limited, Simcyp Division, Level 2-Acero, 1 Concourse Way, Sheffield, S1 2BJ, UK

    Khaled Abduljalil, Masoud Jamei & Trevor N. Johnson

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  1. Khaled Abduljalil
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  2. Masoud Jamei
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Correspondence to Khaled Abduljalil.

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No funding was received for the conduct of this study or the preparation of this article.

Conflict of interest

Khaled Abduljalil, Masoud Jamei, and Trevor N. Johnson are full-time employees of Certara UK Limited. The activities of Certara are supported by a consortium of pharmaceutical companies. The Simcyp Simulators are freely available, following completion of the relevant workshops, to approved members of academic institutions and other non-for-profit organizations for research and teaching purposes.

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Abduljalil, K., Jamei, M. & Johnson, T.N. Fetal Physiologically Based Pharmacokinetic Models: Systems Information on Fetal Blood Components and Binding Proteins. Clin Pharmacokinet 59, 629–642 (2020). https://doi.org/10.1007/s40262-019-00836-3

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