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Treatment During Pregnancy: Gaps in our Knowledge Donald R Mattison Obstetric and Pediatric Pharmacology Research Branch Center for Research for Mothers and Children NICHD, NIH, HHS mattisod@mail.nih.gov 301 451 3823

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treatment during pregnancy gaps in our knowledge

Treatment During Pregnancy:Gaps in our Knowledge

Donald R Mattison

Obstetric and Pediatric Pharmacology Research Branch

Center for Research for Mothers and Children

NICHD, NIH, HHS

mattisod@mail.nih.gov

301 451 3823

slide2

Announcement on SMFM Web Site2nd Annual Summer Institute Maternal-Fetal PharmacologyJuly 23–29, 2006 in Denver, COhttp://www.circlesolutions.com/summerinstitute

  • National Institute of Child Health and Human Development
  • Office of Research on Women’s Health
  • Institute of Human Development, Child and Youth Health
  • Canadian Institutes of Health Research
treatment during pregnancy gaps in our knowledge3
Treatment During Pregnancy:Gaps in our Knowledge
  • Introduction
  • Frequency of Drug Use in Pregnancy
  • Sex Differences in Drug Safety
  • Sex Differences in Pharmacokinetics
  • Case Studies
    • MgSO4
    • Antidepressants
  • Where do we go from here?
slide4

Drug Development

Applied

“In Practice”

Clinical Studies

“Indication”

Basic

3 - 5 years

$350 million

4 years

$45 - 60 million

2 – 4 years

$90 – 150 million

Dosing

and

Safety

Safety

and

Efficacy

Pre-Clinical

Launch

Discovery

Phase IV

Phase I

Phase IIa

Phase IIb

Phase III

  • In Obstetrics and Pediatrics the vast majority of clinical
  • studies (for efficacy and/or safety) are done without knowledge of pharmacokinetics and/or pharmacodynamics
  • ~75% of drugs used in pediatrics not tested in kids
  • most drugs used in women and during pregnancy not tested in either nonpregnant or pregnant women

Submit New Drug Application (NDA)

Apply for Investigational New Drug (IND) Status

obstetric and pediatric pharmacology
Obstetric and Pediatric Pharmacology
  • Pediatric Pharmacology Research Network
    • 13 sites, ~180,000 inpatient, > 2 million outpatient, >200 clinical studies
  • Best Pharmaceuticals for Children Act of 2002
    • Collaboration with 15 ICs: 9 clinical trials, 7 pre-clinical studies
  • Obstetric Pharmacology Research Network
    • Established Fall 2004: 2 clinical trials, 5/40 opportunistic
    • 4 Sites: UTMB, Magee, U Washington, Georgetown
treatment during pregnancy gaps in our knowledge6
Treatment During Pregnancy:Gaps in our Knowledge
  • Introduction
  • Frequency of Drug Use in Pregnancy
  • Sex Differences in Drug Safety
  • Sex Differences in Pharmacokinetics
  • Case Studies of Pharmacokinetics and Pharmacodynamics in Pregnancy
    • MgSO4
    • Antidepressants
  • Where do we go from here?
slide7

AJOG 2003; 188: 1039

  • Identify medications used in rural ob population
  • 28 month study
    • 578 women interviewed across pregnancy
  • 96% of participants given Rx medication
  • 93% self medicated with OTC medication
  • 45% self medicated with Herbal product
slide8

Rx consumed by

women of

reproductive age

in this population

0 12%

1 24%

2 22%

3 16%

≥4 26%

slide9

Therapeutic Class

Antibiotics 35%

Respiratory 14%

GI 13%

Opioids 8%

Rx med use did not

differ by trimester

slide10

OTC

Therapeutic Class

Analgesics

GI

Respiratory

Use of multiple OTC

meds increased across

gestation

slide11

Herbals

  • consumed as
  • “medications” not
  • dietary supplements
  • Many indicated
  • that herbals
  • recommended
  • by health care staff
  • dosing?
  • efficacy?
  • safety?
slide12

Lancet 2000; 356, 1735

  • Survey of records from French Health Insurance Service
    • 1000 women in SW France
    • 99% received Rx during pregnancy
    • mean 13.6 meds per woman
    • 79% received Rx for a drug for which there was no knowledge of safety
slide15

Nature of the drugs may be more worrying

  • than the numbers taken.
  • widespread prescription of meds for which
    • no proven efficacy
    • dosing may not be appropriate for pregnancy
    • no data to evaluate fetal effects
slide16

AJOG 2002; 187: 333

~40% in PDR have pregnancy “risk”

A 0.7%

B 19%

C 66%

D 7%

X 7%

drugs in pregnancy 2004 utmb
Drugs Prescribed

35% Prenatal Vits

18% Antibiotics

16% Fe

5% Topical Creams

5% Antihistamines

4% Analges/Antipyr

FDA Class of Rx

A 1%

B 71%

C 25%

D 1%

X 1%

U 1%

Drugs in Pregnancy – 2004, UTMB
frequency of use and indications
Frequency of Use and Indications
  • Broad multi-agent exposure to Rx, OTC and herbals in women of reproductive age and pregnancy
  • Labeling for dosing, efficacy and safety during pregnancy inadequate
  • Literature resources on dosing, efficacy, safety for women – non-pregnant or pregnant - are not available
treatment during pregnancy gaps in our knowledge19
Treatment During Pregnancy:Gaps in our Knowledge
  • Introduction
  • Frequency of Drug Use in Pregnancy
  • Sex Differences in Drug Safety
  • Sex Differences in Pharmacokinetics
  • Case Studies of Pharmacokinetics and Pharmacodynamics in Pregnancy
    • MgSO4
    • Antidepressants
  • Where do we go from here?
sex differences
Sex Differences
  • Sex differences noted in animal models ~1932
    • F rats required half the dose of barbiturates, compared to M to induce sleep
    • Duration of sleep substantially longer in F given same dose as M
  • Sex differences noted in subsequent studies (pharmacology & toxicology/safety); rat, mouse, rhesus, beagle, cat, rabbit, hamster, goats, cattle, trout, humans
  • Before 1993 under-representation of F in clinical trials was mandated by US FDA
    • Excluded from phase I/II clinical trials and did not encourage participation in later phases
    • Concern focused on two factors; hormonal variations across ovarian cycle & potential for pregnancy
adverse drug reactions
Adverse Drug Reactions

F experience more adverse reactions to drugs than M (GAO, 2001)

  • Evaluated the 10 drugs withdrawn from US market from Jan ’97 – Dec ‘2000
    • Eight had evidence of greater health risks in F identified from post-marketing data
      • 3 introduced before 1993, 5 after 1993
    • Two with no evidence of greater health risks in F using post-marketing data
      • Both introduced after 1993
adverse drug reactions22
Adverse Drug Reactions

F experience more adverse reactions to therapeutic drugs than M

  • F overdosed; pk differences
  • Drug interactions; F take more medications than M
  • Difference is artifact; F report adverse reactions more frequently
  • F experience adverse reactions more frequently; pk, pd differences
adverse drug reactions23
Adverse Drug Reactions

pk differences; F overdosed?

  • Volume of distribution different
  • Hepatic metabolism different?
    • Sex specific CYP’s, drug transporters
    • ~ Half of drugs on market are metabolized by CYP3A, transported by P glycoprotein (liver, GI?)
  • pk modestly successful in predicting adverse drug reactions
adverse drug reactions24
Adverse Drug Reactions

F take more medications than M; drug interactions?

  • F start medication use earlier, contraceptives and reproductive system
  • F use ~60% of all medications
  • Unclear what proportion of adverse events are due to drug interactions
adverse drug reactions25
Adverse Drug Reactions

F report adverse reactions more frequently; difference is artifact?

  • Reports of adverse drug reactions is proportional to drug usage by M, F
  • Adverse reactions reported by F are more severe than those reported by M
adverse drug reactions26
Adverse Drug Reactions

Adverse events reported by F more frequently than by M (FDA database – voluntary reporting of adverse events)

  • Torsades de points
  • QT prolongation
  • Agranulocytosis
  • Bleeding
  • Pancreatitis
  • Renal toxicity
  • Liver toxicity
adverse drug reactions27
Adverse Drug Reactions

Torsades de points, QT prolongation

  • Torsades de points – fatal heart arrhythmia associated with delayed repolarization and prolonged QT
  • Androgens enhance repolarization and shorten QT
    • Decreases M heart susceptibility to QT prolongation effects of drugs
adverse drug reactions28
Adverse Drug Reactions

Acute Liver Failure

  • ~2000 cases/yr in US
  • >50% due to medications
  • ~75% occur in F
    • Fatality rate among F ~80%
  • Unclear if pk or pd differences account for the differential
treatment during pregnancy gaps in our knowledge29
Treatment During Pregnancy:Gaps in our Knowledge
  • Introduction
  • Frequency of Drug Use in Pregnancy
  • Sex Differences in Drug Safety
  • Sex Differences in Pharmacokinetics
  • Case Studies
    • MgSO4
    • Antidepressants
  • Where do we go from here?
pharmacokinetic factors
Pharmacokinetic Factors

Absorption

  • GI:
    • Transit time F≤ M, vary with Progesterone
    • Transit time increased in pregnancy
    • Transport and metabolism systems, P glycoprotein (P-gp)?
  • Skin: F=M
  • Lungs: proportional to respiratory rate and depth
    • F minute ventilation < M
      • Changes during cycle
    • Pregnant F minute ventilation > M (Progesterone)
      • Complain of feeling “short of breath”
      • Inhaled insulin
pharmacokinetic factors31
Pharmacokinetic Factors

Distribution

  • Protein Binding
    • Albumen F≈M
    • Alpha 1 acid glycoprotein F<M,
    • Free fraction drugs F >M
    • Diminished during pregnancy
  • Body Composition
    • Fat content F>M
      • F from 33% to 48% with aging
      • M from 18% to 36% with aging
    • Body water, fat increase across pregnancy
pharmacokinetic factors32
Pharmacokinetic Factors

Metabolism (Data – limited/conflicting)

  • Drug Transporters
    • P-gp M>F, may decrease hepatic metabolism
    • Role in transport and metabolism remains unclear
  • Phase I Enzymes
    • Oxidation
    • CYP3A, overlap in substrates with P-gp
  • Phase II Enzymes
    • Conjugation
    • M≥F, UDP-GT, Sulfotransferases, Methyltransferases
    • M=F, N-Acetyltransferases
sex differences33
Sex Differences

Bioavailability

  • Oral F>M
  • Transdermal M=F
  • Bronchial M>F

Distribution Volume

  • Water Sol M>F
  • Lipid Sol F>M

Protein Binding

  • Albumen F=M
  • Alpha 1 acid gp M>F
sex differences34
Sex Differences

Renal

  • GFR M>F
  • Tubular Secretion M>F
  • Tubular Reabsorption M>F

CYPs – Hepatic and ?others

  • CYP3A F>M
  • CYP2D M>F

Conjugation

  • Glucur, Methyl M>F
  • Acetyl F=M
sex differences35
Sex Differences

Analysis of data submitted to CDER/FDA

  • 28% of data sets demonstrated significant sex differences
  • Sex differences in drug exposure could be greater than 50%
impact of pregnancy pk pd
Impact of Pregnancy – pk/pd
  • Sex differences in pk/pd
    • ADME
  • Pregnancy extends & alters impact on ADME
    • Cardiac output, regional blood flow
    • Body composition, protein binding
    • Transport proteins
    • Phase I and Phase II metabolism
  • Impact on therapeutic strategies
the classic view of pk pd
Pharmacokinetics (PK)

“What the body does to the drug”

Tools generally well developed

Not frequently applied in women, during pregnancy or in children

Pharmacodynamics (PD)

“What the drug does to the body”

Tools are being developed

Clinical relevance

Efficacy

Safety

The “Classic” View of PK-PD
caffeine
Caffeine
  • Water soluble - Vd ↑, []↓
  • Metabolized by CYP1A2* - Metabolism ↓ during pregnancy

Weeks Clearance Half-Life

      • 11 100% 5.3h
      • 17 68% 9.9h
      • 24 54% 12.6h
      • 32 37% 10h
      • PP 100% 5.5h

* Induced by cigarette smoking

slide39

Clin Pharmacol Ther

2001; 70: 121

Caffeine Metabolism

slide40

Clin Pharmacol Ther

2001; 70: 121

Caffeine Metabolism

caffeine metabolism in pregnancy
Caffeine Metabolism in Pregnancy

Metabolic Step Change in Pregnancy

  • Transport proteins ?
  • Phase I metabolism
    • CYP1A2 (M>F) ↓
    • XO (M=F) ↔
    • 8-Hydroxylation (M?F) ↑
  • Phase II metabolism
    • N Acetyltransferase (M=F) ↓
cyp3a4
CYP3A4
  • Most abundant CYP450 in liver and GI
    • 30% of total cytochrome P450
  • Broad substrate specificity
    • Metabolizes >50% of drugs
  • Activity/amount increased during pregnancy
  • Caveats
    • Substrate overlap with P-gp
    • ? Unbound plasma concentration
    • Time course across pregnancy undefined
cyp3a4 examples
CYP3A4 - Examples

Drug Metabolic Change

Nifedipine Clearance (CL) ↑30%

Carbamazepine Concentration ↓18%

Total & unbound [] ↔

Substantial ↓ at term

Midazolam CL ↑

Indinavir AUC ↓ CL ↑ - P-gp?

Lopinavir CL ↑ - P-gp?

Ritonavir Peak/Trough [] ↓ ?binding

cyp2d6
CYP2D6
  • Second most common enzyme responsible for drug metabolism
    • >40 drugs
  • Increases in latter portion of pregnancy
    • Increase only observed in homozygous and heterozygous extensive metabolizers (EM)
    • No change or decrease across pregnancy among poor metabolizers (PM)
cyp2d6 examples
CYP2D6 - Examples

Drug Metabolic Change

Dextromethorphan Metab ↑50% EM

Metab ↓60% PM

Metoprolol CL ↑ w PO admin

Protein binding ↔

Fluoxetine Metab ↑

Nortriptyline CL ↑

phase ii glucuronidation examples
Phase II - Glucuronidation - Examples

Drug Metabolic Change

Lamotrigine CL ↑ 2-3x

(UGT1A4)

Zidovudine CL (↑ 50%) ↔

(UGT2B7)

Morphine CL ↑ 70%

(UGT2B7)

Oxazepam CL ↑ 160%

(UGT2B7, 2B15, 1A9)

pregnancy changes in phase i ii
Increased

CYP3A4

CYP2D6

EM, PM

CYP2C9

CYP2A6

UGT1A4

UGT2B7

Decreased

CYP1A2

Induced smokers

CYP2C19

Pregnancy Changes in Phase I & II
renal elimination
Renal Elimination
  • Drugs Cleared by Renal Mechanisms
    • Ampicillin, Cefuroxime, Ceftazidime, Cephradine, Cefazolin, Piperacillin, Atenolol, Sotalol, Digoxin, Lithium, ….
  • Renal Clearance increases 20% - 60% beginning in first trimester
treatment during pregnancy gaps in our knowledge49
Treatment During Pregnancy:Gaps in our Knowledge
  • Introduction
  • Frequency of Drug Use in Pregnancy
  • Sex Differences in Drug Safety
  • Sex Differences in Pharmacokinetics
  • Case Studies
    • MgSO4
    • Antidepressants
  • Where do we go from here?
the classic view of pk pd50
Pharmacokinetics (PK)

“What the body does to the drug”

Tools generally well developed

Not frequently applied in women, during pregnancy or in children

Pharmacodynamics (PD)

“What the drug does to the body”

Tools are being developed

Clinical relevance

Efficacy

Safety

The “Classic” View of PK-PD
magnesium sulfate
Magnesium Sulfate
  • MgSO4 used to treat seizures, ↑BP for ~75 years
    • Optimum dosing, concentration and therapeutic range undefined
    • Mg bound to proteins ~50%
      • Total vs Free in assays
    • Pk - One vs Two compartment – what does body do to drug
    • Pharmacodynamics – what does drug do to body - BP
mgso 4 therapeutics
MgSO4 Therapeutics
  • 2-Compartment model most appropriate
  • [Mg++] needs to be characterized
  • Disease state alters disposition
  • [Mg++] between 2 – 4 mmol/L produce more than half-maximal reduction in systolic & diastolic BP
treatment during pregnancy gaps in our knowledge63
Treatment During Pregnancy:Gaps in our Knowledge
  • Introduction
  • Frequency of Drug Use in Pregnancy
  • Sex Differences in Drug Safety
  • Sex Differences in Pharmacokinetics
  • Case Studies
    • MgSO4
    • Antidepressants
  • Where do we go from here?
the classic view of pk pd64
Pharmacokinetics (PK)

“What the body does to the drug”

Tools generally well developed

Not frequently applied in women, during pregnancy or in children

Pharmacodynamics (PD)

“What the drug does to the body”

Tools are being developed

Clinical relevance

Efficacy

Safety

The “Classic” View of PK-PD
depression
Depression
  • Depression common in women of reproductive age
    • 10% - 16% during pregnancy
    • 12% - 16% postpartum
  • Necessary to treat
    • Maximize therapeutic efficacy
    • Minimize adverse effects
slide71

Citalopram----------------------Desmethyl-CIT (DMCIT)

CYP 2C19, 2D6, 3A4

DMCIT---------------------Didesmethyl-CIT (DDMCIT)

Oxidative N-demethylation

CYP2D6

ssri s treating maternal depression
SSRI’s Treating Maternal Depression
  • Clinical characterization of SSRI-treated depression - worsening during pregnancy
    • Severity increased at 28 – 32 weeks
    • SSRI dose increased 25% - 80%
  • Increases in maternal CYP 2D6
    • Decrease [SSRI] across pregnancy
    • ? Other metabolic processes, transport
therapeutic goals for obstetrical pharmacology
Therapeutic Goals for Obstetrical Pharmacology
  • Given the class of drugs available what is the drug of choice?
  • How will results of treatment be judged?
    • Clinical signs & symptoms
    • Laboratory tests
  • How will toxicity & side-effects be evaluated?
    • Clinical or laboratory
  • How is treatment duration and schedule determined?
clinical pharmacology for obstetric therapeutics
Clinical Pharmacology for Obstetric Therapeutics
  • Absorption – how does pregnancy influence rate & amount reaching blood?
  • Distribution – how does pregnancy influence how the drug is distributed throughout body to site of therapeutic action & adverse effects?
  • Metabolism – how does pregnancy influence hepatic & renal mechanisms?
  • Elimination – pregnancy influences on clearance?
pharmacodynamics in obstetric therapeutics
Pharmacodynamics in Obstetric Therapeutics
  • Influence of pregnancy on site of action & adverse effects
    • Concentration of drug, metabolites at sites of biological action?
    • Mode or mechanism of action?
    • Impact on signs, symptoms, laboratory test results?
conclusions
Conclusions
  • Research Infrastructure
    • Academic centers with obstetric-pharmacology-basic science collaboration – NICHD - OPRU Network
    • Encourage research exploring ob-pharm
  • Education
    • Educational tools needed
    • Labeling needs to be improved – on both sides of parturition
  • Best practices
    • Therapeutic efficacy for intervention goals are poorly defined
  • Multi-agency effort needed
    • Research & Academic infrastructure – NIH
    • Education, Best Practice – AHRQ
    • Clinical resources – HRSA
    • Safety, efficacy and labeling - FDA
slide77

Announcement on SMFM Web Site2nd Annual Summer Institute Maternal-Fetal PharmacologyJuly 23–29, 2006 in Denver, COhttp://www.circlesolutions.com/summerinstitute

  • National Institute of Child Health and Human Development
  • Office of Research on Women’s Health
  • Institute of Human Development, Child and Youth Health
  • Canadian Institutes of Health Research