Transcript 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 [email protected] 301

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
[email protected]
301 451 3823
Announcement on SMFM Web Site
2nd Annual Summer Institute
Maternal-Fetal Pharmacology
July 23–29, 2006 in Denver, CO
http://www.circlesolutions.com/summerinstitute
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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 Knowledge
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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?
Drug Development
Basic
3 - 5 years
$350 million
Discovery Pre-Clinical
Clinical Studies
“Indication”
4 years
$45 - 60 million
Dosing
and
Safety
Phase I Phase IIa
Applied
“In Practice”
2 – 4 years
$90 – 150 million
Safety
and
Efficacy
Phase IIb Phase III
Launch
Phase IV
In Obstetrics and Pediatrics the vast majority of clinical
studies (for efficacy
and/or safety) are done without
knowledge
of
Submit New
Drug
Apply for Investigational
New Drug
(IND) Status
pharmacokinetics
and/or
pharmacodynamics Application (NDA)
• ~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
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 Knowledge
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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?
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
Rx consumed by
women of
reproductive age
in this population
0
1
2
3
≥4
12%
24%
22%
16%
26%
Therapeutic Class
Antibiotics
Respiratory
GI
Opioids
35%
14%
13%
8%
Rx med use did not
differ by trimester
OTC
Therapeutic Class
Analgesics
GI
Respiratory
Use of multiple OTC
meds increased across
gestation
Herbals
consumed as
“medications” not
dietary supplements
Many indicated
that herbals
recommended
by health care staff
• dosing?
• efficacy?
• safety?
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
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
AJOG 2002; 187: 333
~40% in PDR have
pregnancy “risk”
A
B
C
D
X
0.7%
19%
66%
7%
7%
Drugs in Pregnancy – 2004, UTMB
Drugs Prescribed
FDA Class of Rx
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35% Prenatal Vits
18% Antibiotics
16% Fe
5% Topical Creams
5% Antihistamines
4% Analges/Antipyr
A
B
C
D
X
U
1%
71%
25%
1%
1%
1%
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 Knowledge
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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 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
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 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 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 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 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 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 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 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 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
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 Factors
Distribution
• Protein Binding
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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 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 Differences
Bioavailability
– Oral
– Transdermal
– Bronchial
F>M
M=F
M>F
Distribution Volume
– Water Sol
– Lipid Sol
M>F
F>M
Protein Binding
– Albumen
– Alpha 1 acid gp
F=M
M>F
Sex Differences
Renal
– GFR
– Tubular Secretion
– Tubular Reabsorption
M>F
M>F
M>F
CYPs – Hepatic and ?others
– CYP3A
– CYP2D
F>M
M>F
Conjugation
– Glucur, Methyl
– Acetyl
M>F
F=M
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
• 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
3.5
6
3
5
2.5
Drug Effect
Drug Concentration
7
4
3
2
1.5
2
1
1
0.5
0
0
0
5
10
15
20
25
0
2
Time
• Pharmacokinetics (PK)
• “What the body does to the
drug”
• Tools generally well
developed
– Not frequently applied in
women, during pregnancy or in
children
4
6
8
Drug Concentration
• 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
• 17
• 24
• 32
• PP
100%
68%
54%
37%
100%
* Induced by cigarette smoking
5.3h
9.9h
12.6h
10h
5.5h
Clin Pharmacol Ther
2001; 70: 121
Caffeine Metabolism
Clin Pharmacol Ther
2001; 70: 121
Caffeine Metabolism
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
• 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
Drug
Metabolic Change
Nifedipine
Clearance (CL) ↑30%
Carbamazepine Concentration ↓18%
Total & unbound [] ↔
Substantial ↓ at term
Midazolam
CL ↑
Indinavir
Lopinavir
Ritonavir
AUC ↓ CL ↑ - P-gp?
CL ↑ - P-gp?
Peak/Trough [] ↓ ?binding
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
Drug
Dextromethorphan
Metoprolol
Fluoxetine
Nortriptyline
Metabolic Change
Metab ↑50% EM
Metab ↓60% PM
CL ↑ w PO admin
Protein binding ↔
Metab ↑
CL ↑
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
Decreased
• CYP3A4
• CYP2D6
• CYP1A2
– EM, PM
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CYP2C9
CYP2A6
UGT1A4
UGT2B7
– Induced smokers
• CYP2C19
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 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-PD
3.5
6
3
5
2.5
Drug Effect
Drug Concentration
7
4
3
2
1.5
2
1
1
0.5
0
0
0
5
10
15
20
25
0
2
Time
• Pharmacokinetics (PK)
• “What the body does to the
drug”
• Tools generally well
developed
– Not frequently applied in
women, during pregnancy or in
children
4
6
8
Drug Concentration
• 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
PreTermLabor
Free
Total
PreEclampsia
Free
Total
Volume of
Distribution
Elimination
Half-life
15,775 mL
577 min
15,667 mL
610 min
16,675 mL
313 min
24,260 mL
707 min
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 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-PD
3.5
6
3
5
2.5
Drug Effect
Drug Concentration
7
4
3
2
1.5
2
1
1
0.5
0
0
0
5
10
15
20
25
0
2
Time
• Pharmacokinetics (PK)
• “What the body does to the
drug”
• Tools generally well
developed
– Not frequently applied in
women, during pregnancy or in
children
4
6
8
Drug Concentration
• 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
Fluoxetine -------------------------- Norfluoxetine
Oxidative N-demethylation
CYP2D6
Citalopram----------------------Desmethyl-CIT (DMCIT)
CYP 2C19, 2D6, 3A4
DMCIT---------------------Didesmethyl-CIT (DDMCIT)
Oxidative N-demethylation
CYP2D6
SSRI’s Treating Maternal Depression
• Clinical characterization of SSRItreated 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
• 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
• 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
• 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
• 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
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Research & Academic infrastructure – NIH
Education, Best Practice – AHRQ
Clinical resources – HRSA
Safety, efficacy and labeling - FDA
Announcement on SMFM Web Site
2nd Annual Summer Institute
Maternal-Fetal Pharmacology
July 23–29, 2006 in Denver, CO
http://www.circlesolutions.com/summerinstitute
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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