2. Pregnancy PBPK modeling
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Tasnif et al., 2016. doi: 10.1002/cpt.382
Pregnancy is associated with profound anatomical and physiological changes that
can substantially alter drug pharmacokinetics (PK), e.g.:
3. Pregnancy PBPK modeling
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Dallmann et al., 2018. doi: 10.1002/cpt.1084
During the past years, PBPK models have been increasingly developed and
applied to pregnant women
More than 60 pregnancy PBPK models have been reported for >40 drugs
4. Pregnancy PBPK modeling
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Enzyme or transporter involved in main elimination pathway
Of these published models:
• Approx. 1/3 was developed for drugs predominantly metabolized via CYP3A4
• Approx. 1/3 was developed for drugs eliminated via the kidneys
• Phase II enzymes, especially UGTs, were rarely addressed
Dallmann et al., 2019. doi: 10.2174/1381612825666190320135137
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UGT expression
The human UGT1 gene contains 13 individual promotor regions/unique first exons
The most important members of the UGT1 family are:
Individual exons (1 out of 13 exons is
transcribed into mRNA)
Shared exons (all are
transcribed into mRNA)
Mackenzie et al., 2005. doi: 10.1097/01.fpc.0000173483.13689.56
• UGT1A1
• UGT1A6
• UGT1A4
• UGT1A6
The UGT2 gene contains exons that are not shared between family members
The most important member of the UGT2 family is UGT2B7
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UGT1A1/4 expression during pregnancy
Estimation of unbound intracellular
hormone concentrations in vivo
Estimation of UGT1A1/4
induction in vivo
Verification through PBPK models
In vitro induction of UGT1A1
and UGT1A4 by progesterone
and estradiol, respectively
In vivo plasma concentration of
progesterone and estradiol
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UGT1A1/4 expression during pregnancy
The unbound intracellular fraction of progesterone and estradiol is a sensitive
parameter that dramatically affects the estimated -fold change
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UGT1A1/4 expression during pregnancy
Algorithm for selection of adequate compounds
• Bilirubin
• Bisphenol A
• Dolutegravir
• Labetalol
• Lamotrigine
• Paracetamol
• Propofol
• Raltegravir
Develop
PBPK
model
Exogenous
UGT1A1/4
substrate?
Are all fm
known?
Change in
all clearance
pathways
known?
Available
PK data in
pregnant
women?
• Bisphenol A
• Dolutegravir
• Labetalol
• Lamotrigine
• Paracetamol
• Propofol
• Raltegravir
• Bisphenol A
• Dolutegravir
• (Labetalol)
• Lamotrigine
• Raltegravir
• Bisphenol A
• (Labetalol)
• Lamotrigine
• (Labetalol)
• Lamotrigine
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Labetalol PBPK model
UGT2B7
(~35%)
UGT1A1
(~15%)
Alton et al., 1994. PMID: 7895603; Hopkins et al. 1976. PMID: 1001750
CYP2C19 (?)
(~50% ?)
Unchanged renal excretion
(< 5%)
Elimination of labetalol
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Labetalol PBPK model
Labetalol model for non-pregnant subjects
Observed data from: Awni et al., 1988. doi: 10.1002/j.1552-4604.1988.tb03156.x; Daneshmend & Roberts, 1982. doi: 10.1111/j.1365-
2125.1982.tb04936.x; Lalonde et al., 1990. doi: 10.1038/clpt.1990.187; Mäntylä et al., 1980. doi: 10.1111/j.1365-2125.1980.tb01076.x;
McNeil et al., 1979. doi: 10.1111/j.1365-2125.1979.tb04773.x.
IV administration Single and multiple oral dose administration
19. Conclusion
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Pregnancy-induced changes in UGT expression are poorly understood
Mechanistic elucidation of these changes is complicated by lacking information on:
• PK data of compounds metabolized by UGTs in pregnant women
• Dose fraction metabolized
• Effect of pregnancy on parallel elimination pathways
• Fraction unbound of estradiol/progesterone in hepatocytes
Based on preliminary analyses, semi-quantitative insights can be gained:
• No change can be expected for UGT2B7
• Induction is likely for UGT1A1; maximum induction is ~4.9-fold
• Induction is likely for UGT1A4; maximum induction is ~3.0-fold