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Clinical Therapeutics in Obstetrics. 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 [email protected]

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Pregnancy and Prescription Medication Use: Quantifying Maternal, Placental and Fetal Pharmacology

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Pregnancy and prescription medication use quantifying maternal placental and fetal pharmacology l.jpg

Clinical Therapeutics in Obstetrics

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

[email protected]


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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-exposure-response

    • Balance detail with utility

2


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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


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Considerations for

clinical therapeutics:

Do pk and pd change during pregnancy?

Role of the placenta:

Drug metabolism,

Transport,

Target

  • Formal drug development process

  • Drugs used in pregnancy are developed informally,

  • migrating into use for:

    • Maternal disease

    • Fetal disease

    • Placental dysfunction

4


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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?


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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

6


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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


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Adapted from Panek P, et al. Curr Drug Metab 2009;10:520


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Hematological Changes During Pregnancy

Gabbe et al 2007


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Cardiovascular Changes During Pregnancy

Gabbe et al 2007


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Pulmonary Changes During Pregnancy

8.8


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Renal Changes During Pregnancy


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Placental Changes During Pregnancy

Surface area

Increases from 3.2 m2 at 28 weeks to 12.6 m2 at term

Distance between maternal and fetal blood

Decreases from 50 – 100 u at 2nd month to 4 – 5 u at term

Blood Flow

Increases from 50 ml/min at 10 weeks to 600 ml/min at term

13

13


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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


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Young et al 1997


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Young et al 1997


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Translating Fetal Neurodevelopmental Stages Across Species

  • Neurodevelopmental Stages

  • Sequence of neurodevelopmentalevents is conserved

  • Completion of neurodevelopmentalevents prior to birth varies acrossspecies

  • Timing of conception, birth and neurodevelopment species specific

  • Other tissues, organs, biologicalfunctions may also vary

  • Biological accuracy greatest uncertainty

Clancy et al 2001


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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

18


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  • 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

Luecke et al 1994


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(Andrew et al 2008)


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Maternal PB/PK Model

(Placenta and Fetus)

Gaohua et al 2010


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General PB/PK Models Used in Pregnancy

Corley et al 2003


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Corley et al 2003


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Glucose Transport

Gude et al 2004

Schneider et al 2003

Illsley 2000


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Myllynen et al 2009


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(Behravan et al 2007)


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Saquinavir + P-gp inhibitors

Saquinavir

Molsa et al 2005


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Caffeine Disposition in Pregnancy: Simcyp

  • Simulation parameters

  • Non-pregnant

  • 36 Weeks gestation

  • 150 mg caffeine

  • Pregnancy changescardiovascular, adipose,renal, metabolic, etc

  • Pregnancy compartment:placenta, fetus, amnioticfluid, mammary

Gaohua et al 2010


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Caffeine

Water soluble - Vd ↑, [ ]↓

Metabolized by CYP1A2, XO, NAT

Overall clearance ↓ during pregnancy

WeeksClearance

11100%

17 68%

24 54%

32 37%

PP100%


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  • Assessment of CYP1A2 Activity

  • Apparent oral clearance of caffeinedecreased during pregnancy

  • Suggesting CYP1A2 activity decreased during pregnancy

(Tracy et al 2005)


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Physiological accuracyis generally easier thanbiological accuracy

Adding biologically andphysiologically relevantinformation enhances

predictions

Gaohua et al 2010


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Case Examples:Treating the MomTreating the PlacentaTreating the Fetus


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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


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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


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Prophylaxis

Treatment


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Early Data: Oseltamivir Carboxylate

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.


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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


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38

  • Shintaku et al 2007, 2009, 2011


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  • Relative Risk for DA Constriction:

  • Diclofenac > Salicylic Acid, Antipyrine

  • Case reports of DA Constriction:

  • Diclofenac > Salicylic Acid, Antipyrine

  • Shintaku et al 2007, 2009, 2011

39


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Case Examples:Treating the MomTreating the PlacentaTreating the Fetus


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Malaria: Treating the Placenta

  • Adverse impact

    • Pregnancy 2nd 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)


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Malaria in Pregnancy

Placental infection

  • Placental Infection

  • Protected site

  • p falciparium

  • Necrosis

  • Growth restriction

Desai et al 2007


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Case Examples:Treating the MomTreating the PlacentaTreating the Fetus


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Ito 2001


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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


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Hebert et al 2008


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(Behravan et al 2007)


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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


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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


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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


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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, AminRostami-Hodjegan, ManoChetty

  • Developmental Timescales

    • Barbara Clancy


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