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Research ArticleArticle

Development of a Novel Maternal-Fetal Physiologically Based Pharmacokinetic Model II: Verification of the Model for Passive Placental Permeability Drugs

Zufei Zhang and Jashvant D. Unadkat
Drug Metabolism and Disposition August 2017, 45 (8) 939-946; DOI: https://doi.org/10.1124/dmd.116.073957
Zufei Zhang
Department of Pharmaceutics, University of Washington, Seattle, Washington
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Jashvant D. Unadkat
Department of Pharmaceutics, University of Washington, Seattle, Washington
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Abstract

Fetal exposure to drugs cannot be readily estimated from single time point cord blood sampling at the time of delivery. Therefore, we developed a physiologically based pharmacokinetic (PBPK) model to estimate fetal drug exposure throughout pregnancy. In this study, we report verification of this novel maternal-fetal PBPK (m-f-PBPK) model for drugs that passively diffuse across the placenta and are not metabolized/transported there. Our recently built m-f-PBPK model was populated with gestational age-dependent changes in maternal drug disposition and maternal-fetal physiology. Using midazolam as an in vivo calibrator, the transplacental passive diffusion clearance of theophylline and zidovudine was first estimated. Then, for verification, the predicted maternal plasma (MP) and umbilical venous (UV) plasma drug concentrations by our m-f-PBPK were compared against those observed at term. Overall, our m-f-PBPK model well predicted the maternal and fetal exposure to the two verification drugs, theophylline and zidovudine, at term, across a range of dosing regimens, with nearly all observed MP and UV plasma drug concentrations falling within the 90% prediction interval [i.e., 5th–95th percentile range of a virtual pregnant population (n = 100)]. Prediction precision and bias of theophylline MP and UV were 14.5% and 12.4%, and 9.4% and 7.5%, respectively. Furthermore, for zidovudine, after the exclusion of one unexpectedly low MP concentration, prediction precision and bias for MP and UV were 50.3% and 30.2, and 28.3% and 15.0%, respectively. This m-f-PBPK should be useful to predict fetal exposure to drugs, throughout pregnancy, for drugs that passively diffuse across the placenta.

Footnotes

    • Received October 18, 2016.
    • Accepted December 29, 2016.
  • This work was supported by National Institutes of Health National Institute on Drug Abuse [Grant P01DA032507].

  • https://doi.org/10.1124/dmd.116.073957.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 45 (8)
Drug Metabolism and Disposition
Vol. 45, Issue 8
1 Aug 2017
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Research ArticleArticle

Verification of a Maternal-Fetal PBPK Model

Zufei Zhang and Jashvant D. Unadkat
Drug Metabolism and Disposition August 1, 2017, 45 (8) 939-946; DOI: https://doi.org/10.1124/dmd.116.073957

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Research ArticleArticle

Verification of a Maternal-Fetal PBPK Model

Zufei Zhang and Jashvant D. Unadkat
Drug Metabolism and Disposition August 1, 2017, 45 (8) 939-946; DOI: https://doi.org/10.1124/dmd.116.073957
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