Fetal Physiologically Based Pharmacokinetic Models: Systems Information on the Growth and Composition of Fetal Organs

Abstract

Background: The growth of fetal organs is a dynamic process involving considerable changes in the anatomical and physiological parameters that can alter fetal exposure to xenobiotics in utero. Physiologically based pharmacokinetic models can be used to predict the fetal exposure as time-varying parameters can easily be incorporated.

Objective: The objective of this study was to collate, analyse and integrate the available time-varying parameters needed for the physiologically based pharmacokinetic modelling of xenobiotic kinetics in a fetal population.

Methods: We performed a comprehensive literature search on the physiological development of fetal organs. Data were carefully assessed, integrated and a meta-analysis was performed to establish growth trends with fetal age and weight. Algorithms and models were generated to describe the growth of these parameter values as functions of age and/or weight.

Results: Fetal physiologically based pharmacokinetic parameters, including the size of the heart, liver, brain, kidneys, lungs, spleen, muscles, pancreas, skin, bones, adrenal and thyroid glands, thymus, gut and gonads were quantified as a function of fetal age and weight. Variability around the means of these parameters at different fetal ages was also reported. The growth of the investigated parameters was not consistent (with respect to direction and monotonicity).

Conclusion: Despite the limitations identified in the availability of some values, the data presented in this article provide a unique resource for age-dependent organ size and composition parameters needed for fetal physiologically based pharmacokinetic modelling. This will facilitate the application of physiologically based pharmacokinetic models during drug development and in the risk assessment of environmental chemicals and following maternally administered drugs or unintended exposure to environmental toxicants in this population.