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Treatment During Pregnancy: Gaps in our Knowledge

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Title: Treatment During Pregnancy: Gaps in our Knowledge


1
Treatment During PregnancyGaps in our Knowledge
  • Donald R Mattison
  • Obstetric and Pediatric Pharmacology Research
    Branch
  • Center for Research for Mothers and Children
  • NICHD, NIH, HHS
  • mattisod_at_mail.nih.gov
  • 301 451 3823

2
Announcement on SMFM Web Site2nd Annual Summer
Institute Maternal-Fetal Pharmacology July
2329, 2006 in Denver, COhttp//www.circlesolutio
ns.com/summerinstitute
  • National Institute of Child Health and Human
    Development
  • Office of Research on Womens Health
  • Institute of Human Development, Child and Youth
    Health
  • Canadian Institutes of Health Research

3
Treatment During PregnancyGaps 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?

4
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
5
Obstetric and Pediatric Pharmacology
  • Pediatric Pharmacology Research Network
  • 13 sites, 180,000 inpatient, gt 2 million
    outpatient, gt200 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

6
Treatment During PregnancyGaps 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?

7
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

8
Rx consumed by women of reproductive age in this
population 0 12 1 24 2 22 3 16 4 26
9
Therapeutic Class Antibiotics 35 Respiratory 14
GI 13 Opioids 8 Rx med use did not differ
by trimester
10
OTC Therapeutic Class Analgesics GI Respiratory
Use of multiple OTC meds increased
across gestation
11
  • Herbals
  • consumed as
  • medications not
  • dietary supplements
  • Many indicated
  • that herbals
  • recommended
  • by health care staff
  • dosing?
  • efficacy?
  • safety?

12
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

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  • 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

16
AJOG 2002 187 333
40 in PDR have pregnancy risk A 0.7 B 19
C 66 D 7 X 7
17
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

18
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

19
Treatment During PregnancyGaps 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?

20
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

21
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

22
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

23
Adverse Drug Reactions
  • pk differences F overdosed?
  • Volume of distribution different
  • Hepatic metabolism different?
  • Sex specific CYPs, 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

24
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

25
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

26
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

27
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

28
Adverse Drug Reactions
  • Acute Liver Failure
  • 2000 cases/yr in US
  • gt50 due to medications
  • 75 occur in F
  • Fatality rate among F 80
  • Unclear if pk or pd differences account for the
    differential

29
Treatment During PregnancyGaps 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?

30
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 FM
  • Lungs proportional to respiratory rate and depth
  • F minute ventilation lt M
  • Changes during cycle
  • Pregnant F minute ventilation gt M (Progesterone)
  • Complain of feeling short of breath
  • Inhaled insulin

31
Pharmacokinetic Factors
  • Distribution
  • Protein Binding
  • Albumen FM
  • Alpha 1 acid glycoprotein FltM,
  • Free fraction drugs F gtM
  • Diminished during pregnancy
  • Body Composition
  • Fat content FgtM
  • F from 33 to 48 with aging
  • M from 18 to 36 with aging
  • Body water, fat increase across pregnancy

32
Pharmacokinetic Factors
  • Metabolism (Data limited/conflicting)
  • Drug Transporters
  • P-gp MgtF, 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
  • MF, UDP-GT, Sulfotransferases,
    Methyltransferases
  • MF, N-Acetyltransferases

33
Sex Differences
  • Bioavailability
  • Oral FgtM
  • Transdermal MF
  • Bronchial MgtF
  • Distribution Volume
  • Water Sol MgtF
  • Lipid Sol FgtM
  • Protein Binding
  • Albumen FM
  • Alpha 1 acid gp MgtF

34
Sex Differences
  • Renal
  • GFR MgtF
  • Tubular Secretion MgtF
  • Tubular Reabsorption MgtF
  • CYPs Hepatic and ?others
  • CYP3A FgtM
  • CYP2D MgtF
  • Conjugation
  • Glucur, Methyl MgtF
  • Acetyl FM

35
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

36
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

37
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

38
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

39
Clin Pharmacol Ther 2001 70 121
Caffeine Metabolism
40
Clin Pharmacol Ther 2001 70 121
Caffeine Metabolism
41
Caffeine Metabolism in Pregnancy
  • Metabolic Step Change in Pregnancy
  • Transport proteins ?
  • Phase I metabolism
  • CYP1A2 (MgtF) ?
  • XO (MF) ?
  • 8-Hydroxylation (M?F) ?
  • Phase II metabolism
  • N Acetyltransferase (MF) ?

42
CYP3A4
  • Most abundant CYP450 in liver and GI
  • 30 of total cytochrome P450
  • Broad substrate specificity
  • Metabolizes gt50 of drugs
  • Activity/amount increased during pregnancy
  • Caveats
  • Substrate overlap with P-gp
  • ? Unbound plasma concentration
  • Time course across pregnancy undefined

43
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

44
CYP2D6
  • Second most common enzyme responsible for drug
    metabolism
  • gt40 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)

45
CYP2D6 - Examples
  • Drug Metabolic Change
  • Dextromethorphan Metab ?50 EM
  • Metab ?60 PM
  • Metoprolol CL ? w PO admin
  • Protein binding ?
  • Fluoxetine Metab ?
  • Nortriptyline CL ?

46
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)

47
Pregnancy Changes in Phase I II
  • Increased
  • CYP3A4
  • CYP2D6
  • EM, PM
  • CYP2C9
  • CYP2A6
  • UGT1A4
  • UGT2B7
  • Decreased
  • CYP1A2
  • Induced smokers
  • CYP2C19

48
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

49
Treatment During PregnancyGaps 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?

50
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

51
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

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Volume of Distribution Elimination Half-life
PreTermLabor Free 15,775 mL 577 min
Total 15,667 mL 610 min
PreEclampsia Free 16,675 mL 313 min
Total 24,260 mL 707 min
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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

63
Treatment During PregnancyGaps 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?

64
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

65
Depression
  • Depression common in women of reproductive age
  • 10 - 16 during pregnancy
  • 12 - 16 postpartum
  • Necessary to treat
  • Maximize therapeutic efficacy
  • Minimize adverse effects

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Fluoxetine --------------------------?
Norfluoxetine Oxidative N-demethylation CYP2D6

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Citalopram----------------------?Desmethyl-CIT
(DMCIT) CYP 2C19, 2D6, 3A4 DMCIT---------------
------?Didesmethyl-CIT (DDMCIT) Oxidative
N-demethylation CYP2D6
72
SSRIs 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

73
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?

74
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?

75
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?

76
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

77
Announcement on SMFM Web Site2nd Annual Summer
Institute Maternal-Fetal Pharmacology July
2329, 2006 in Denver, COhttp//www.circlesolutio
ns.com/summerinstitute
  • National Institute of Child Health and Human
    Development
  • Office of Research on Womens Health
  • Institute of Human Development, Child and Youth
    Health
  • Canadian Institutes of Health Research
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