Presented by Dr. André Dallmann Open-Systems-Pharmacology.org

1. Open-Systems-Pharmacology.org
Analysis of UGT induction during pregnancy
through PBPK modeling
Dr. André Dallmann

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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UGT expression
AhR: arylhydrocarbon receptor
CAR: constitutive androstane receptor
E2: estrogen
FXR: farnesoid X receptor
HNF1α: hepatocyte nuclear factor 1α
HNF4α: hepatocyte nuclear factor 4α
hPXR: human pregnane X receptor
LXR: liver X receptor
P4: progesterone
PPAR-α: Peroxisome proliferator-activated
receptor-α
UGT1A1 UGT1A9 UGT2B7UGT1A4UGT1A3 UGT1A6
PPAR-α
hPXR
HNF1α
HNF4α
AhR
FXR
LXR
CAR
P4
E2
E2

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UGT1A1/4 expression in vitro
Observed data from:
Jeong et al., 2008. doi: 10.1080/00498250701744633
Observed data from:
Chen et al., 2009. doi: 10.1124/dmd.109.026609

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Estradiol / progesterone plasma
concentrations during pregnancy

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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

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Labetalol PBPK model
Observeddatafrom:
Fischeratal.,2014.doi:10.1007/s40262-013-0123-0
Labetalol model for pregnant subjects

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Lamotrigine PBPK model
Elimination of lamotrigine
Doig et al., 1991. PMID: 1795036; Beck et al., 2006. PMID: 17038873
Unchanged renal excretion
(~10%)
UGT1A4
(80 – 90%)
(<0.5%)
(<0.5%)
(10%)

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Lamotrigine PBPK model
Lamotrigine model for non-pregnant subjects
Observeddatafrom:Dooseetal.,2003.doi:10.1046/j.1528-
1157.2003.64402.x;Incecayiretal.,2007.doi:10.1055/s-0031-
1296641;Sidhuetal.,2006.doi:10.1111/j.1365-2125.2006.02598.x;
Woottonetal.,1997.doi:10.1111/j.1365-2125.1997.tb00133.x

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Lamotrigine PBPK model
Observeddatafrom:
Pennelletal.,2004.doi:10.1212/01.WNL.0000103286.47129.F8
Lamotrigine model for pregnant subjects

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Lamotrigine PBPK model
Observeddatafrom:
Reimersetal.,2011.doi:10.1016/j.eplepsyres.2011.02.002
Lamotrigine model for pregnant subjects

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

20. Open-Systems-Pharmacology.org
Thank you

21. Backup
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22. Backup
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UGT1A1 induction: 4.0-fold

23. Backup
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UGT1A1 induction: 1.6-fold