Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Analysis of UGT induction during pregnancy through PBPK modeling


Published on

Presented by Dr. André Dallmann

Published in: Health & Medicine
  • Login to see the comments

  • Be the first to like this

Analysis of UGT induction during pregnancy through PBPK modeling

  1. 1. Analysis of UGT induction during pregnancy through PBPK modeling Dr. André Dallmann
  2. 2. Pregnancy PBPK modeling Page 2 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. 3. Pregnancy PBPK modeling Page 3 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. 4. Pregnancy PBPK modeling Page 4 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
  5. 5. Page 5 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
  6. 6. Page 6 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
  7. 7. Page 7 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
  8. 8. Page 8 Estradiol / progesterone plasma concentrations during pregnancy
  9. 9. Page 9 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
  10. 10. Page 10 UGT1A1/4 expression during pregnancy The unbound intracellular fraction of progesterone and estradiol is a sensitive parameter that dramatically affects the estimated -fold change
  11. 11. Page 11 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
  12. 12. Page 12 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
  13. 13. Page 13 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
  14. 14. Page 14 Labetalol PBPK model Observeddatafrom: Fischeratal.,2014.doi:10.1007/s40262-013-0123-0 Labetalol model for pregnant subjects
  15. 15. Page 15 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%)
  16. 16. Page 16 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
  17. 17. Page 17 Lamotrigine PBPK model Observeddatafrom: Pennelletal.,2004.doi:10.1212/01.WNL.0000103286.47129.F8 Lamotrigine model for pregnant subjects
  18. 18. Page 18 Lamotrigine PBPK model Observeddatafrom: Reimersetal.,2011.doi:10.1016/j.eplepsyres.2011.02.002 Lamotrigine model for pregnant subjects
  19. 19. Conclusion Page 19 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. 20. Thank you
  21. 21. Backup Page 21
  22. 22. Backup Page 22 UGT1A1 induction: 4.0-fold
  23. 23. Backup Page 23 UGT1A1 induction: 1.6-fold