Pregnancy-PBPK models: How are biochemical and physiological processes integrated?

Abstract

Physiologically based pharmacokinetic (PBPK) modeling is used to predict the pharmacokinetic behavior of xenobiotics in humans. During pregnancy, anatomical and physiological parameters are modified leading to toxicokinetics’ changes of substances in the body. Considering these physiological parameters change in the building processes of pregnancy PBPK (p-PBPK) model is essential to have accurate estimates of tissue/organ concentrations for the pregnant women but also for the fetus.

The review aims to summarize which specific processes are considered in the building of p-PBPK models and may be useful at the early stages of p-PBPK modeling.

To achieve this objective, a literature search focusing on anatomical, physiological, and biochemical parameters impacted by pregnancy was conducted. Most of the time, p-PBPK models do not include all the specific processes identified but only the most impacting ones on the global kinetics, depending mainly on the substance of interest. Allometric relations were identified to be classically included in the pregnancy models to describe the modifications induced by pregnancy to overcome the lack of data usually observed for the gestation. However, more and more data are gathered for pregnancy leading to the introduction of more data-based equations in PBPK modeling.

The most common strategy for p-PBPK development is based on the development of adult PBPK models that are then adapted to specific populations such as pregnant women. The adult PBPK model structure is modified to account for the pregnancy by adding specific compartments of fetal development and also specific compartments that are impacted during the pregnancy such as fat or mammary glands. Extrapolation of pregnant rat model is the other common strategy option used more specifically for environmental substances.

Overall, further data on maternal and fetal pharmacokinetics are needed to validate the xenobiotic exposure predictions during pregnancy, using for example in vitro, in vivo or ex vivo experiments.