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transfer clearance for the single cotyledon is scaled to the whole placenta and
then integrated in a PBPK model. Using this approach, pharmacokinetics in
the umbilical vein observed at delivery in the third trimester could be
adequately predicted for several drugs, including acyclovir, emtricitabine,
tenofovir, and nevirapine.
286–288
Other approaches for informing placental drug transfer in a PBPK model
that circumvent the use of the ex vivo placental perfusion experiment have
also been proposed in the literature. For example, Zhang and Unadkat have
suggested an approach for drugs crossing the placenta exclusively via passive
diffusion that relies on the drug’s apparent membrane permeability measured,
for example, in Caco-2 cells.
289
Specifically, the authors developed an
empirical equation for scaling the transplacental passive diffusion clearance
of midazolam to other drugs by means of their apparent membrane
permeability that was reported in the literature. Integration of the scaled
diffusion clearances in a PBPK model showed that the pharmacokinetics of
theophylline and zidovudine could be adequately predicted in the umbilical
vein at term delivery. Recently, Codaccioni et al. elegantly reviewed various
placental transfer submodels and approaches to inform the relevant transfer
parameters in PBPK models that have been applied to both animals and
humans.
290
SUMMARY
Although tremendous advancements have been made in elucidating the
anatomic and physiologic changes in the placenta, there remains a gap in
identifying all transporters and their interaction with different exogenous and
endogenous compounds at the interface between the mother and the fetus.
Understanding the mechanism behind placental transport and metabolism is
paramount as more pregnant women are receiving medical therapy throughout
their pregnancy. This empowers clinicians to better tailor drug therapy used
for treating maternal medical conditions and minimize fetal exposure. In
addition, dosing adjustments to some medications are made with the intention
to treat fetal conditions and minimize maternal toxicity. Adding to this
complexity is the fact that maternal diseases can also contribute to changes in
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transporter expression and may alter physiologic pathways occurring at the
cellular level.
The use of in vitro and in vivo studies to explore the pharmacokinetics
and pharmacodynamics of drugs and enumerate the fetal-to-maternal ratio has
been a cornerstone in pharmacometric studies. Newer techniques such as the
placenta-on-a-chip uses a microengineered interface made to mimic the
syncytiotrophoblast membrane, with expression and production of transports
and molecule bathed in an environment similar to the physiologic matrix in the
human placenta. This would help identify drugs that can cross the placental
barrier and the mechanism governing the process in hopes that this
information can be taken into consideration when prescribing medical therapy
for pregnant patients and ensuring patient safety and reducing fetotoxicity.
ACKNOWLEDGMENTS
This work was supported by the National Heart, Lung and Blood Institute
grant to HKA (K23HL141640).
The authors express the gratitude to Dr. Anthony Scialli for his assistance
in reviewing the manuscript. The authors deeply acknowledge the insightful
contributions of Nada Djokanociv, Rada Boskovic, Gideon Koren, Olga
Zharikova, Tatiana Nanovskaya, and Mahmoud S. Ahmed in preparing the
previous versions of this chapter.
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