Treatment During Pregnancy: Gaps in our Knowledge

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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

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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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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?

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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
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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

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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?

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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

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

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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

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

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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

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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?

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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?

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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

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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

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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

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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

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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

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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

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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

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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

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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

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Clin Pharmacol Ther 2001 70 121
Caffeine Metabolism
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Clin Pharmacol Ther 2001 70 121
Caffeine Metabolism
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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) ?

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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

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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

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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)

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CYP2D6 - Examples

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

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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)

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Pregnancy Changes in Phase I II

• Increased
• CYP3A4
• CYP2D6
• EM, PM
• CYP2C9
• CYP2A6
• UGT1A4
• UGT2B7

• Decreased
• CYP1A2
• Induced smokers
• CYP2C19

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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

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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

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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

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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

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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
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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

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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?

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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?

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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?

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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