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Analysis of UGT induction during pregnancy through PBPK modeling

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

Published in: Health & Medicine
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Analysis of UGT induction during pregnancy through PBPK modeling

  1. 1. Open-Systems-Pharmacology.org Analysis of UGT induction during pregnancy through PBPK modeling Dr. André Dallmann
  2. 2. Pregnancy PBPK modeling www.open-systems-pharmacology.org 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 www.open-systems-pharmacology.org 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 www.open-systems-pharmacology.org 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. www.open-systems-pharmacology.org 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. www.open-systems-pharmacology.org 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. www.open-systems-pharmacology.org 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. www.open-systems-pharmacology.org Page 8 Estradiol / progesterone plasma concentrations during pregnancy
  9. 9. www.open-systems-pharmacology.org 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. www.open-systems-pharmacology.org 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. www.open-systems-pharmacology.org 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. www.open-systems-pharmacology.org 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. www.open-systems-pharmacology.org 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. www.open-systems-pharmacology.org Page 14 Labetalol PBPK model Observeddatafrom: Fischeratal.,2014.doi:10.1007/s40262-013-0123-0 Labetalol model for pregnant subjects
  15. 15. www.open-systems-pharmacology.org 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. www.open-systems-pharmacology.org 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. www.open-systems-pharmacology.org Page 17 Lamotrigine PBPK model Observeddatafrom: Pennelletal.,2004.doi:10.1212/01.WNL.0000103286.47129.F8 Lamotrigine model for pregnant subjects
  18. 18. www.open-systems-pharmacology.org Page 18 Lamotrigine PBPK model Observeddatafrom: Reimersetal.,2011.doi:10.1016/j.eplepsyres.2011.02.002 Lamotrigine model for pregnant subjects
  19. 19. Conclusion www.open-systems-pharmacology.org 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. Open-Systems-Pharmacology.org Thank you
  21. 21. Backup www.open-systems-pharmacology.org Page 21
  22. 22. Backup www.open-systems-pharmacology.org Page 22 UGT1A1 induction: 4.0-fold
  23. 23. Backup www.open-systems-pharmacology.org Page 23 UGT1A1 induction: 1.6-fold

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