Pregnancy and prescription medication use quantifying maternal placental and fetal pharmacology
Download
1 / 52

Pregnancy and Prescription Medication Use: Quantifying Maternal, Placental and Fetal Pharmacology - PowerPoint PPT Presentation


  • 108 Views
  • Uploaded on
  • Presentation posted in: General

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 Donald.Mattison@nih.hhs.gov.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha

Download Presentation

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

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


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

Donald.Mattison@nih.hhs.gov


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 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


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

  • 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 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 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


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


Hematological Changes During Pregnancy

Gabbe et al 2007


Cardiovascular Changes During Pregnancy

Gabbe et al 2007


Pulmonary Changes During Pregnancy

8.8


Renal 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

  • 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


Young et al 1997


Young et al 1997


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 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


  • 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


(Andrew et al 2008)


Maternal PB/PK Model

(Placenta and Fetus)

Gaohua et al 2010


General PB/PK Models Used in Pregnancy

Corley et al 2003


Corley et al 2003


Glucose Transport

Gude et al 2004

Schneider et al 2003

Illsley 2000


Myllynen et al 2009


(Behravan et al 2007)


Saquinavir + P-gp inhibitors

Saquinavir

Molsa et al 2005


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

Water soluble - Vd ↑, [ ]↓

Metabolized by CYP1A2, XO, NAT

Overall clearance ↓ during pregnancy

WeeksClearance

11100%

17 68%

24 54%

32 37%

PP100%


  • Assessment of CYP1A2 Activity

  • Apparent oral clearance of caffeinedecreased during pregnancy

  • Suggesting CYP1A2 activity decreased during pregnancy

(Tracy et al 2005)


Physiological accuracyis generally easier thanbiological accuracy

Adding biologically andphysiologically relevantinformation enhances

predictions

Gaohua et al 2010


Case Examples:Treating the MomTreating the PlacentaTreating the Fetus


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

  • 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


Prophylaxis

Treatment


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 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

  • Shintaku et al 2007, 2009, 2011


  • 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


Case Examples:Treating the MomTreating the PlacentaTreating the Fetus


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)


Malaria in Pregnancy

Placental infection

  • Placental Infection

  • Protected site

  • p falciparium

  • Necrosis

  • Growth restriction

Desai et al 2007


Case Examples:Treating the MomTreating the PlacentaTreating the Fetus


Ito 2001


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


Hebert et al 2008


(Behravan et al 2007)


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

  • 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

  • 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

  • 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


ad
  • Login