PBPK Modeling Approach to Predict the Behavior of Drugs Cleared by Metabolism in Pregnant Subjects and Fetuses

This study aimed to develop a physiologically based pharmacokinetic (PBPK) model that simulates metabolically cleared compounds' pharmacokinetics (PK) in pregnant subjects and fetuses. This model accounts for the differences in tissue sizes, blood flow rates, enzyme expression levels, plasma pr...

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Published inPharmaceutics Vol. 16; no. 1; p. 96
Main Authors Le Merdy, Maxime, Szeto, Ke Xu, Perrier, Jeremy, Bolger, Michael B, Lukacova, Viera
Format Journal Article
LanguageEnglish
Published Switzerland MDPI AG 01.01.2024
MDPI
Subjects
Analysis
Clinical trials
Computer software industry
Drug dosages
Enzymes
Females
Fetuses
Gestational age
in silico
Lamotrigine
Liver
metabolic clearance
Metabolism
Metabolites
Metronidazole
PBPK
Physiological aspects
Physiology
Pregnancy
Pregnant women
Simulation
United States
PBPK
metabolic clearance
in silico
pregnancy
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Summary:This study aimed to develop a physiologically based pharmacokinetic (PBPK) model that simulates metabolically cleared compounds' pharmacokinetics (PK) in pregnant subjects and fetuses. This model accounts for the differences in tissue sizes, blood flow rates, enzyme expression levels, plasma protein binding, and other physiological factors affecting the drugs' PK in both the pregnant woman and the fetus. The PBPKPlus™ module in GastroPlus was used to model the PK of metoprolol, midazolam, and metronidazole for both non-pregnant and pregnant groups. For each of the three compounds, the model was first developed and validated against PK data in healthy non-pregnant volunteers and then applied to predict the PK in the pregnant groups. The model accurately described the PK in both the non-pregnant and pregnant groups and explained well the differences in the plasma concentration due to pregnancy. When available, the fetal plasma concentration, placenta, and fetal tissue concentrations were also predicted reasonably well at different stages of pregnancy. The work described 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 metabolically cleared compounds.
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ISSN:1999-4923
1999-4923
DOI:10.3390/pharmaceutics16010096