Abstract
The purpose of this study was to develop a physiologically based pharmacokinetic (PBPK) model predicting the pharmacokinetics (PK) of different compounds in pregnant subjects. This model considers the differences in tissue sizes, blood flow rates, enzyme expression levels, glomerular filtration rates, plasma protein binding, and other factors affected during pregnancy in both the maternal and fetal models. The PBPKPlus™ module in GastroPlus® was used to model the PK of cefuroxime and cefazolin. For both compounds, the model was first validated against PK data in healthy non-pregnant volunteers and then applied to predict pregnant groups PK. The model accurately described the PK in both non-pregnant and pregnant groups and explained well differences in the plasma concentration due to pregnancy. The fetal plasma and amniotic fluid concentrations were also predicted reasonably well at different stages of pregnancy. This work describes the use of a PBPK approach for drug development and demonstrates the ability to predict differences in PK in pregnant subjects and fetal exposure for compounds excreted renally. The prediction for pregnant groups is also improved when the model is calibrated with postpartum or non-pregnant female group if such data are available.
Highlights
The impact of medication used during pregnancy on both maternal and fetal health is a growing public health concern with the steady increase of medication intake over the last three decades
The purpose of this research was to develop and validate a physiologically based pharmacokinetic (PBPK) model predicting the maternal and fetal PK of various active pharmaceutical ingredients (APIs) administered to women during different stages of pregnancy
The physiological changes incorporated in the model as a function of maternal age, pre-pregnancy weight, gestational age (GA), and tissue changes are briefly described and all model specific equations are presented in supplementary materials 1 and 2
Summary
The impact of medication used during pregnancy on both maternal and fetal health is a growing public health concern with the steady increase of medication intake over the last three decades. Guest Editors: Diane Burgess, Marilyn Morris and Meena Subramanyam [3,4] For this reason, non-clinical studies (in animals and in vitro cell or tissue experiments) are the most prominent sources of information during the drug development period to assess drug safety in this population [5,6]. Modification of body composition and impact on the cardiovascular, digestive, and renal systems can significantly alter the pharmacokinetics of an API Because of these safety concerns and lack of specific dose adjustments, both the pregnant woman and the fetus are exposed to an increased risk of incorrect pharmacotherapy with sub- or supratherapeutic drug exposure leading to toxic effects in the woman and/or fetus. The use of physiologically based pharmacokinetic (PBPK) modeling has emerged as a comprehensive tool to
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