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2. Clinical Therapeutics in Obstetrics. IntroductionChallenges for mechanistic models in pregnancySex differences in pharmacokinetics and pharmacodynamicsDynamics of maternal organism adapting to pregnancyDynamics of growth and development of the placentaDynamics of growth and development of th

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pregnancy and prescription medication use quantifying maternal placental and fetal pharmacology
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]

clinical therapeutics in obstetrics
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

clinical therapeutics in obstetrics3
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
slide4
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

drugs in development
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?
clinical therapeutics in obstetrics6
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

clinical therapeutics in obstetrics7
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

placental changes during pregnancy
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

translating fetal developmental time from experimental species to humans
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
slide17
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

clinical therapeutics in obstetrics18
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

slide19
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

slide21
Maternal PB/PK Model

(Placenta and Fetus)

Gaohua et al 2010

slide24
Glucose Transport

Gude et al 2004

Schneider et al 2003

Illsley 2000

slide27
Saquinavir + P-gp inhibitors

Saquinavir

Molsa et al 2005

slide28
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

caffeine
Caffeine

Water soluble - Vd ↑, [ ]↓

Metabolized by CYP1A2, XO, NAT

Overall clearance ↓ during pregnancy

Weeks Clearance

11 100%

17 68%

24 54%

32 37%

PP 100%

slide30
Assessment of CYP1A2 Activity
  • Apparent oral clearance of caffeinedecreased during pregnancy
  • Suggesting CYP1A2 activity decreased during pregnancy

(Tracy et al 2005)

slide31
Physiological accuracyis generally easier thanbiological accuracy

Adding biologically andphysiologically relevantinformation enhances

predictions

Gaohua et al 2010

influenza during pregnancy treating the mom
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
oseltamivir
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
slide35
Prophylaxis

Treatment

early data oseltamivir carboxylate
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.

use of nsaids in pregnancy
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

slide38
38
  • Shintaku et al 2007, 2009, 2011
slide39
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

malaria treating the placenta
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)
slide42
Malaria in Pregnancy

Placental infection

  • Placental Infection
  • Protected site
  • p falciparium
  • Necrosis
  • Growth restriction

Desai et al 2007

digoxin toxicity
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

clinical therapeutics in pregnancy clinical trials
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
inclusion in clinical trials
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
key issues
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
acknowledgments
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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