1. Pregnancy and Prescription Medication Use: Quantifying Maternal, Placental and Fetal Pharmacology Donald R Mattison Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH Donald.Mattison@nih.hhs.gov Clinical Therapeutics in Obstetrics

2. 2 Introduction Challenges for mechanistic models in pregnancy –Sex differences in pharmacokinetics and pharmacodynamics –Dynamics of maternal organism adapting to pregnancy –Dynamics of growth and development of the placenta –Dynamics of growth and development of the fetus Improve precision and decrease uncertainty in predicting dose-exposure-response –Balance detail with utility

3. 3 Clinical Therapeutics in Obstetrics Three concerns for obstetrical clinical therapeutics –Dosing Achieving “therapeutic concentrations” at the target site(s) –Efficacy/Effectiveness Does the “therapeutic concentration” produce the desired effect(s) –Safety What are the adverse consequences of exposure below, at, or above the “therapeutic concentration” Biologically relevant models –Study design –Concentration and response at various target sites Mother, Placenta or Fetus

4. 4 Formal drug development process Drugs used in pregnancy are developed informally, migrating into use for: Maternal disease Fetal disease Placental dysfunction Considerations for clinical therapeutics: Do pk and pd change during pregnancy? Role of the placenta: Drug metabolism, Transport, Target

5. Drugs in development Search of the PhRMA database of new medicines in development in the US (03 January 2011) –Hypertension in pregnancy: none –Preeclampsia: none –Gestational diabetes: none –Uterine hemorrhage: none –Labor pain: none –Obstetric and gynecological infection: none –Preterm labor: five –Labor disorders: none –Morning sickness: one –Neonatal infection: none –Neonatal jaundice: none –Respiratory distress syndrome: one EMEA?

6. 6 Clinical Therapeutics in Obstetrics Introduction Challenges for mechanistic models in pregnancy –Sex differences in pharmacokinetics and pharmacodynamics –Dynamics of maternal organism adapting to pregnancy –Dynamics of growth and development of the placenta –Dynamics of growth and development of the fetus Improve precision and decrease uncertainty in predicting dose-response –Balance detail with utility

7. 7 Clinical Therapeutics in Obstetrics Introduction Challenges for mechanistic models in pregnancy –Sex differences in pharmacokinetics and pharmacodynamics –Dynamics of maternal organism adapting to pregnancy –Dynamics of growth and development of the placenta –Dynamics of growth and development of the fetus Improve precision and decrease uncertainty in predicting dose-response –Balance detail with utility

8. Weight Gain during Pregnancy Cumulative Increase in Weight (g) Tissues and Fluids 10 Weeks20 Weeks30 Weeks40 Weeks Fetus53001,5003,400 Placenta20170430650 Amniotic fluid30350750800 Uterus140320600970 Breasts45180360405 Blood1006001,3001,450 Extravascular fluid030801,480 Maternal stores (fat)3102,0503,4803,345 Total6504,0008,50012,500 Adapted from Panek P, et al. Curr Drug Metab 2009;10:520

9. 9 Gabbe et al 2007 Hematological Changes During Pregnancy

10. 10 Gabbe et al 2007 Cardiovascular Changes During Pregnancy

11. 11 Pulmonary Changes During Pregnancy 8.8

12. Renal Changes During Pregnancy

13. 13 Placental Changes During Pregnancy Surface area –Increases from 3.2 m 2 at 28 weeks to 12.6 m 2 at term Distance between maternal and fetal blood –Decreases from 50 – 100 u at 2 nd month to 4 – 5 u at term Blood Flow –Increases from 50 ml/min at 10 weeks to 600 ml/min at term

14. 14 Translating Fetal Developmental Time from Experimental Species To Humans –Allometric relationships –Proportion of gestation –Proportion of development Robinson & Dreher 1990 –Comparison of anatomical stages Carnegie stages, Bayer et al. 1993 –Vulnerability patterns Dobbing & colleagues 1970’s

15. 15 Young et al 1997

16. 16 Young et al 1997

17. 17 Clancy et al 2001 Translating Fetal Neurodevelopmental Stages Across Species Neurodevelopmental Stages Sequence of neurodevelopmental events is conserved Completion of neurodevelopmental events prior to birth varies across species Timing of conception, birth and neurodevelopment species specific Other tissues, organs, biological functions may also vary Biological accuracy greatest uncertainty

18. 18 Clinical Therapeutics in Obstetrics Introduction Challenges for mechanistic models in pregnancy –Sex differences in pharmacokinetics and pharmacodynamics –Dynamics of maternal organism adapting to pregnancy –Dynamics of growth and development of the placenta –Dynamics of growth and development of the fetus Improve precision and decrease uncertainty in predicting dose-response –Balance detail with utility

19. 19 Luecke et al 1994 Model Parameters Parent Compound and one metabolite Maternal – 27 compartments Fetal – 16 compartments Physiologically complete Biologically incomplete Dynamic with respect to: Maternal organism Placenta Fetus

20. 20 (Andrew et al 2008)

21. 21 Maternal PB/PK Model Gaohua et al 2010 (Placenta and Fetus)

22. 22 Corley et al 2003 General PB/PK Models Used in Pregnancy

23. 23 Corley et al 2003

24. Gude et al 2004 Illsley 2000 Glucose Transport Schneider et al 2003

25. 25 Myllynen et al 2009

26. 26 (Behravan et al 2007)

27. 27 Molsa et al 2005 Saquinavir Saquinavir + P-gp inhibitors

28. 28 Caffeine Disposition in Pregnancy: Simcyp Gaohua et al 2010 Simulation parameters Non-pregnant 36 Weeks gestation 150 mg caffeine Pregnancy changes cardiovascular, adipose, renal, metabolic, etc Pregnancy compartment: placenta, fetus, amniotic fluid, mammary

29. 29 Caffeine Water soluble - Vd ↑, [ ]↓ Metabolized by CYP1A2, XO, NAT Overall clearance ↓ during pregnancy WeeksClearance 11100% 17 68% 24 54% 32 37% PP100%

30. 30 (Tracy et al 2005) Assessment of CYP1A2 Activity Apparent oral clearance of caffeine decreased during pregnancy Suggesting CYP1A2 activity decreased during pregnancy

31. 31 Gaohua et al 2010 Adding biologically and physiologically relevant information enhances predictions Physiological accuracy is generally easier than biological accuracy

32. Case Examples: Treating the Mom Treating the Placenta Treating the Fetus

33. Influenza during pregnancy: Treating the Mom Increased morbidity and mortality from influenza during pregnancy Oseltamivr recommended medication at doses used in adults –No data on pharmacokinetics or pharmacodynamics in pregnancy –Dosing, efficacy and safety not described Design a study to define how to effectively treat the mother

34. Oseltamivir Pro-drug –Metabolized by carboxylesterases to active drug oseltamivir carboxylate (OC) –Disposition Absorption –Substrate for GI PEPT1 Active drug –Formed by hepatic carboxylesterase 1 Distribution –Oseltamivir ~40% protein bound, OC ~5% –Oseltamivir substrate for P-gp »Very little access to fetal circulation »Placental perfusion studies –OC substrate for OAT3 (Slc22a8), MRP4 (Abcc4) Elimination –Glomerular filtration –Tubular secretion –Blocked by probenecid

35. ProphylaxisTreatment

36. Early Data: Oseltamivir Carboxylate ActualSimulation Apparent Oral Clearance (P:NP) 1.41.5 Area under the concentration *time curve (P:NP) 0.7 Beigi, R. H.; Han, K.; Venkataramanan, R.; Hankins, G. D.; Clark, S.; Hebert, M. F.; Easterling, T.; Zajicek, A.; Ren, Z.; Mattison, D. R.; Caritis, S. N., Pharmacokinetics of oseltamivir among pregnant and nonpregnant women. Am J Obstet Gynecol 2011.

37. Use of NSAIDS in pregnancy Use of NSAIDS is common Use in pregnancy carries fetal and neonatal risk –Constriction of ductus arteriosis –Persistant pulmonary hypertension Use of human placental perfusion data for risk assessment and clinical support –Antipyrene –Salicylic acid –Diclofenac (monocarboxylate transporter) –Shintaku et al 2007, 2009, 2011 37

38. 38 Shintaku et al 2007, 2009, 2011

39. 39 Relative Risk for DA Constriction: Diclofenac > Salicylic Acid, Antipyrine Case reports of DA Constriction: Diclofenac > Salicylic Acid, Antipyrine Shintaku et al 2007, 2009, 2011

40. Case Examples: Treating the Mom Treating the Placenta Treating the Fetus

41. Malaria: Treating the Placenta Adverse impact –Pregnancy 2 nd high-risk group after children Maternal Placental Fetal Therapy/prevention –Little data on dosing, efficacy, safety “The kinetics, safety, and efficacy of available antimalarial drugs are poorly documented because pregnant women are systematically excluded from clinical trials” –Nosten, McGready and Mutabingwa Lancet Infectious Diseases 2007 Failure of therapy high during pregnancy –Clear blood but after stopping treatment the infection re- emerges (genetic analysis)

42. Malaria in Pregnancy Desai et al 2007 Placental infection Placental Infection Protected site p falciparium Necrosis Growth restriction

44. Case Examples: Treating the Mom Treating the Placenta Treating the Fetus

45. Ito 2001

46. Digoxin Toxicity Digoxin used to treat heart disease for >200 yrs –High rate of toxicity Up to 30% if not carefully monitored Among those with digoxin toxicity –47% had life-threatening arrythmia –41% mortality –Therapeutic monitoring Aarnoudse et al (2007) conducted a prospective population based study –Women at ~2x greater risk than men –Not known if pregnancy alters risk

47. Hebert et al 2008

48. (Behravan et al 2007)

49. Clinical Therapeutics in Pregnancy: Clinical Trials Pregnancy does not diminish decision making capacity Institute of Medicine (1994) –“…pregnant women be presumed eligible for participation in clinical studies” Many IRBs and investigators consider pregnancy or reproductive age – exclusion criteria Others suggest that exclusion is unethical –Dosing, efficacy, safety? Only concern about clinical therapeutics during pregnancy is fetal safety

50. Inclusion in Clinical Trials Declaration of Helsinki –No mention of research in pregnancy 2002 Ethical Guidelines for Biomedical Research Involving Human Subjects –Guideline 17 –Pregnant women should be presumed eligible UNAIDS/WHO ethical guidelines –…women throughout the lifespan…pregnant or breastfeeding…recipients of safe and effective interventions –How are “safe and effective interventions” identified? Exclusion of women from research will deny them any benefit from the research

51. 51 Key Issues Clinical therapeutics across the course of development (prenatal, perinatal and postnatal) is challenging –Neglected in pregnancy PK, PD changes across pregnancy are likely to may make typical adult doses toxic or inadequate –Enhanced training and research in clinical therapeutics in pregnancy needed internationally –Perinatal drug development – preclinical and clinical represents unique opportunity in pharmacology and developmental biology Ethics of inclusion or exclusion

52. 52 Acknowledgments Oseltamivir –Richard Beigi, Steve Caritis, Raman Venkataramanan, NICHD Obstetric-Fetal Pharmacology Research Units Pregnancy pharmacokinetics –Maisa Feghali Simcyp, Simulink, Caffeine, Sample size –L. Gaohua, Amin Rostami-Hodjegan, Mano Chetty Developmental Timescales –Barbara Clancy