Empirical Models for Anatomical and Physiological Changes in a Human Mother and Fetus During Pregnancy and Gestation

Abstract

Many parameters treated as constants in traditional physiologically based pharmacokinetic models must be formulated as time-varying quantities when modeling pregnancy and gestation due to the dramatic physiological and anatomical changes that occur during this period. While several collections of empirical models for such parameters have been published, each has shortcomings. We sought to create a repository of empirical models for tissue volumes, blood flow rates, and other quantities that undergo substantial changes in a human mother and her fetus during the time between conception and birth, and to address deficiencies with similar, previously published repositories. We used maximum likelihood estimation to calibrate various models for the time-varying quantities of interest, and then used the Akaike information criterion to select an optimal model for each quantity. For quantities of interest for which time-course data were not available, we constructed composite models using percentages and/or models describing related quantities. In this way, we developed a comprehensive collection of formulae describing parameters essential for constructing a PBPK model of a human mother and her fetus throughout the approximately 40 weeks of pregnancy and gestation. We included models describing blood flow rates through various fetal blood routes that have no counterparts in adults. Our repository of mathematical models for anatomical and physiological quantities of interest provides a basis for PBPK models of human pregnancy and gestation, and as such, it can ultimately be used to support decision-making with respect to optimal pharmacological dosing and risk assessment for pregnant women and their developing fetuses. The views expressed in this article are those of the authors and do not necessarily represent the views or policies of the U.S. Environmental Protection Agency.\n\nAUTHOR SUMMARYPhysiologically based pharmacokinetic modeling is a well-known technique for making predictions about internal time-course concentrations of a substance that has entered an organism. This tool is widely used in both pharmaceutical research and human health risk assessment because it harnesses one of the fundamental tenets of both pharmacology and toxicology: it is the concentrations of an active chemical that reach internal target tissues, rather than externally applied \"doses\", that govern the extent of the response (whether beneficial or adverse). Constructing physiologically based pharmacokinetic models for pregnancy and gestation presents a considerable challenge because many of the required parameters (such as blood flow rates or tissue volumes) that are typically assumed to be constant in adult models or short-duration simulations cannot be assumed to be constant when modeling pregnancy. Here we present models, stated as functions of gestational age, for anatomical and physiological changes that occur in a human mother and fetus during pregnancy and gestation. We evaluated and selected models by applying a consistent statistical technique, and where possible, we compared results produced by our models to those produced by previously-published models. The collection of pregnancy parameter models presented here represents the most comprehensive such collection to date.