Abstract
Determining fetal drug exposure (except at the time of birth) is not possible for both logistical and ethical reasons. Therefore, we developed a novel maternal-fetal physiologically based pharmacokinetic (m-f-PBPK) model to predict fetal exposure to drugs and populated this model with gestational age–dependent changes in maternal-fetal physiology. Then, we used this m-f-PBPK to: 1) perform a series of sensitivity analyses to quantitatively demonstrate the impact of fetoplacental metabolism and placental transport on fetal drug exposure for various drug-dosing regimens administered to the mother; 2) predict the impact of gestational age on fetal drug exposure; and 3) demonstrate that a single umbilical venous (UV)/maternal plasma (MP) ratio (even after multiple-dose oral administration to steady state) does not necessarily reflect fetal drug exposure. In addition, we verified the implementation of this m-f-PBPK model by comparing the predicted UV/MP and fetal/MP AUC ratios with those predicted at steady state after an intravenous infusion. Our simulations yielded novel insights into the quantitative contribution of fetoplacental metabolism and/or placental transport on gestational age–dependent fetal drug exposure. Through sensitivity analyses, we demonstrated that the UV/MP ratio does not measure the extent of fetal drug exposure unless obtained at steady state after an intravenous infusion or when there is little or no fluctuation in MP drug concentrations after multiple-dose oral administration. The proposed m-f-PBPK model can be used to predict fetal exposure to drugs across gestational ages and therefore provide the necessary information to assess the risk of drug toxicity to the fetus.
Footnotes
- Received January 25, 2017.
- Accepted May 25, 2017.
↵1 Current affiliation: Merck Sharp & Dohme Corp., Kenilworth, New Jersey.
↵2 Current affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California.
The current work was supported by National Institutes of Health National Institute on Drug Abuse [Grant P01DA032507]. Z.Z. was supported by the Office of Women's Health, US Food and Drug Administration [ORISE Fellowship] for part of the submitted work. No other potential conflicts of interest relevant to this article are reported.
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- Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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