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Presented at FDA training session on October 17, 2002.
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Reproductive Toxicology: History and State of Regulatory Science
Joseph F. Holson, Ph.D.WIL Research Laboratories, Inc.
Where We Are and How We Got There…Introductory Lecture on Reproductive
Toxicology
CTE/CDER
October 17, 2002
Experimental and Epidemiologic Vigilance are our only Safeguards
When I thought I was dying and my hands were numb and wouldn't work-- and my father was dying too--when the villagers turned against us--it was to the sea I would go to cry. No one can understand why I love the sea so much. The sea has never abandoned me. The sea is the blood of my veins.
Tomoko Uemura
“Chrontogeny” of Reproductive Toxicology
1891
1979
1998
Return of Thalidomide
Effects on Eggs(Dareste)
1855
1997
FDAMA
1996
FQPASWDA
1959
1962
Thalidomide Epidemic
1982
Isotretinoin Approved
1967
First Pregnancy Registry (Atlanta)
1974
First National Pregnancy Registry
1966
1940 First FDA Laboratory Animal Safety Studies
Rubella Epidemic(Gregg)
1941
1981
First ACE-Fetopathy
Case Report
1993
“ACE-Fetopathy”
Coined
Goldenthal Guidelines
1971
DES (Herbst & Scully)
Wilson’s Principles 1963
Conference on Prenatal Drug
Effects
NCTR Collaborative Behavioral
Study
NCTR Collaborative
Study Reported
1985
NCTR Concordance
Study (Teratology vs. Developmental
Toxicology)
Ongoing Methylmercury
and DES Exposures
1973
DBCP
1975
Red Dye No. 2
1906
USDA Bureau of Chemistry
International Concern on Decreasing
Fertility
1992
Agent Orange/2,4,5-T
& TCDD
Karnofsky
1950
Litigation continues - Involves forseeability
Medical community believed DES promoted
progesterone synthesis by FPU
First randomized control study with
placebo: safe but no efficacy
Present
(Walker - Mouse) Numerous experimental
studies to develop a good animal model
Litigation
Karnaby Clinical Studies Apparent safety at high doses
Green, et al., Intersexuality
in mice
SYNTHESISfirst orally
active estrogen mimic
DES-Vaginal CCA link in 8 young women (15-22 years)
Debate about DES use in cattle and residues in meat
1971Herbst & Scully
Not considered a teratogenKalter & Warkany
Prescribed to prevent spontaneous abortion
Based on Smith
Gabriel-RobezCleft Palates and heart
defects in mice
Wilson’s Principles of Teratology
1. Susceptibility to Teratogenesis depends on the genotype of the conceptus and the manner in which this interacts with adverse environmental factors
2. Susceptibility to Teratogenesis varies with the developmental stage at the time of exposure to an adverse influence
3. Teratogenic agents act in specific ways (mechanisms) on developing cells and tissues to initiated sequences of abnormal developmental events (pathogenesis)
4. The access of adverse influences to developing tissues depends on the nature of the influence (agent)
5. The four manifestations of deviant development are death, malformation, growth retardation, and functional deficit
6. Manifestations of deviant development increase in frequency and degree as dosage increases, from the no-effect to the totally lethal level
Possible Inter-relationships of Developmental Toxicity Endpoints
Toxic Stimulus
Malformations
Functional Impairments
Growth Retardation
Death
Toxic Stimulus GrowthRetardation Death
Malformation
Functional Impairment
Percent Change Percent ChangeFetal Weight Embryolethality
5 10 5 10
Mice A/J 84 22 1176 324 C57BL/6 198 50 992 228 CDI 84 22 805 235
Rats CDb 52 16 858 248 OMc 44 12 723 216
Number of Litters (N)a to Detect Changesin Fetal Weights and Deaths in Mice and Rats
aNumber of litters/groupbCharles River, Wilmington, MAcOsborne-Mendel, Charles River, Wilmington, MA
From Nelson and Holson, 1978
Animal:Human Concordance Studiesfor Prenatal Toxicity
Nisbet & Karch, 1983 Many chemicalsRelied on authors’ conclusionsEmphasis on fertilityNo measures of internal dose
Attributes
Interdisciplinary team Criteria for acceptance of data/conclusionsConcept of multiple developmental toxicology endpoints No measures of internal dose
Authors
Holson et al., 1981 (Tox Forum)Kimmel et al., 1984 (NCTR Report)
Attributes
Interspecies inhalatory doses adjustedRelied on authors’ conclusions23 occupational chemicals and mixtures No measures of internal dose
Provided detailed informationOnly 4 drugsEmphasis on morphologyFocus on NOAELsNo measures of internal dose
Many chemicals and agentsVariably relied on authors’ conclusionsNo measures of internal dose nor criteria for inclusion or exclusion of studies
Authors
Hemminki & Vineis, 1985
Newman et al., 1993
Schardein, 1995 & 2000*
Animal:Human Concordance Studiesfor Prenatal Toxicity
*Misnomer to refer to thousands of experimental developmental toxicants
Awareness of Developmental Toxicity of Selected Agents
Agent Year First Reported Species*
Alcohol(ism)
Aminopterin
Cigarette Smoking
Diethylstilbestrol
Heroin/Morphine
Ionizing Radiation
Methylmercury
Polychlorinated Biphenyls
Steroidal Hormones
Thalidomide
1957
1950
1941
1940
1969
1950
1953
1969
1943
1961
(gp), ch, hu, mo, rat
(mo & rat), ch, hu
(rab), hu, rat
(rat), hu, mi, mo
(rat), ha, hu, rab
(mo), ha, hu, rat, rab
(rat), ca, hu, mo
(hu), rat
(monk), ha, hu, mo, rat, rab
(hu), mo, monk, rab
*ca - cat, ch - chicken, ha - hamster, gp - guinea pig, hu - human, mi - mink, mo - mouse, monk - monkey, rat - rat, rab - rabbit
Effect-Levels for Teratogensin Humans and Test Species
Aminopterin Death/Malformations
Death/Malformations
Agent ResponseHuman
Rat
Species Dose0.1 mg/kg/da
0.1 mg/kg
Diethylstilbestrol Genital Tract Abnormalities/Death
Genital Tract Abnormalities/Death
Human
Mouse
0.8-1.0 mg/kg
1 mg/kg
Ionizing Radiation Malformations
Malformations
Human
Rat/Mouse
20 rads/da
10-20 rads/da
Cigarette Smoking Growth Retardation
Growth Retardation
Human
Rats
>20 cigarettes/da
>20 cigarettes/da
Thalidomide Malformations
Malformations
Malformations
Human
Monkey
Rabbit
0.8-1.7 mg/kg
5.0-45 mg/kg
150 mg/kg
What is Meant by Maternal Toxicity?
No universally accepted definition Varies among laboratories and regulatory agencies
Broad range of severity in endpoints Maternal deaths (~10%) Minimal changes in weight gain (as low as 5%)
Endpoints used to define should vary depending on species Rat vs. rabbit
Why is Maternal Toxicity Important?
Pregnant female provides physical environment, nutrients, and metabolic waste disposal
Perturbation of the maternal physiological state can impact the well-being of her embryos
Relationship between Maternal Toxicity and Fetal Outcome in Humans
Embryo/fetal toxicity in presence of overt maternal toxicity Aminopterin Methylmercury Polychlorinated biphenyls
Embyro/fetal toxicity in presence of maternal stress (physiological changes) Steroidal hormones Ethanol Cigarette smoking
Embryo/fetal toxicity without significant maternal effects Thalidomide Accutane Diethylstilbestrol Ionizing radiation
Comparative Early Placentation
Amniotic Cavity
Extra-Embryonic Coelom
Decidua
Yolk Sac
Uterine Lumen
Uterine Artery
Decidua
Ectoplacenta
Allantois
Visceral Yolk Sac
Vascular Lacuna
Human Conceptus (Pre-Chorioallantoic Placental Stage) Day 10 Rat Conceptus
The inverted yolk sac surrounds rodent embryo but not human
Comparative Definitive Placentation
Amniotic Cavity
Extra-Embryonic Coelom
DeciduaYolk Sac
Uterine Artery
Decidua
Re-EstablishedUterine Lumen
Amniotic Cavity
Visceral Yolk Sac
VascularLacuna
Human Conceptus at the Time of Chorioallantoic Placental Establishment Day 12 Rat Conceptus
ChorioallantoicPlacenta
ChorioallantoicPlacenta
YSP may be site of effect in rodents not existent in human conceptus
Establishment of theUteroplacental Circulation
Yolk Sac (YS) contained within chorion and not directly exposed to chemicals in maternal tissues and blood
YS
Human Teratogens
Why do we know so little? Early wastage of severely affected embryos Human exposure information is not well documented Human exposures may be extremely low Readily recognizable and consistent lesions are rare Other types of reproductive problems may be related,
but not thoroughly investigated Population monitoring is limited Testing of environmental chemicals and
pharmaceuticals identified potential agents Pregnant women frequently choose to avoid
exposure to many substances
Human Epidemiology Studies vs. Experimental Animal Assessments
Less rigorously monitoredGreater phenotypic heterogeneityLess amenable to dose-response
evaluationsRamifications of endpoints better
ascertainedRetrospective studies plagued with recall
bias
Terminology
Developmental deviation
Structural changeMalformationAnomalyCongenital defect
Anatomical alteration
TerataStructural aberrationDeformationVariation
(minor vs. normal)
Observational Determinants of Anatomical/Functional Deviations
Degree of deviation from averageIncidence (prevalence)*Impact on salubrityCosmetic significance
*In humans convention of <4%; no medical or surgical significance has been used
*In experimental studies, no convention used – statistical
FDA Definition
Rare Event – “an endpoint that occurs in less than 1 percent of the control animals in a study and in historical control animals”
Reviewer Guidance(Draft)
Integration of Study Results to AssessConcerns About Human Reproductive
And Developmental Toxicities
CDER, 10/2001Pharmacology/Toxicity
Comparison of Overall Spontaneous Malformation Rates in Different Species
Multiple Surveys3-94.0Human
* Actual number in laboratory population ~44,000
1675.3-5.75.5Dog
47080-103.2Rabbit
52070-31.2Mouse
96430-1.60.33Rat*
NRange (%)Mean %Species
Rare Events (Low-Incidence Findings): Typical Reaction to, and Subsequent Scenario
Disbelief, rely on statistical insignificanceComparison to concurrent controlComparison to historical control (HC)Comparison to other HC databasesAsk experience/opinions of othersConstruct explanation to negateAgency rejectsRe-do study or label appropriately
Freehand Section
Whole-Body Microdissection
½ Skeletal ½ Visceral 100%
Guideline minimum = 25%, 175 + 175 vs. 1400
4 Groups
(of 25 Dams)X
350 Fetuses =1400 Fetuses
½ & ½ Control and High Group (per guideline)
Size Comparison at Near Term
CR Length 75 mmCR Length 35 mm
3.6 grams 47 grams
CR Length 19 mm
1.3 grams
RabbitRatMouse
Taylor, 1986
Case Study: Dystocia, Extended Parturition and/or Pregnancy
2-generation with second mating phase of F1, vapor inhalation, used industrially, OTC pharmaceutically
0/121/181/2100F1-2nd
1/170000F1-1st
3/262/24000F0
700500300700PPM
HC then: 2/333 = 0.60%HC now: 4/1100 = 0.36%
Case Study: Malformation Example Topical Antibiotic for Oral Mucosa
MaxMinMean% PL
TotalMalformation
0.3%PL0.0% PL0.02%2/9643Retroesophageal Aortic Arch
Historical Control Data
4321Malformation
1 (0.3%PL)1 (0.3%PL)00Retroesophageal Aortic Arch
Rat Study Data
Selected Reproductive Endpoints Exhibiting Strong Signals from Rare Events/Low Incidence
6.5g strong signal
1 is equivocal 2 is more significant signal
91%
decrease of 1
Mean = 7.0g 0.23 range 6.5-7.4g n = 1100 litters
Newborn Pup Weights
Mean = 0.94% (10/1061)
Total Litter Loss
Mean = 96.2% Min/Max 91-95%
Mortality PND 4
13.9 1.02Mean Viable Litter Size
Examples from WIL Research Historical Control in Crl:CD(SD)IGS BR
Endpoint
Rare Events: Control vs. Treated Groups
3
1
3:1 Probability that spontaneous event will occur in treated group
Paradigm to Evaluate Rare Findings
Comparison to concurrent control Evaluate dose-responsiveness including TK, AUC/Cmax Compare to HC range and mean, consider other statistical tests,
including Monte-Carlo Analysis Evaluate signals of developmental toxicity among dose groups Compare to second species Compare to findings in the combined pre-/postnatal study Perform confirmatory study:
Increasing N Increasing number of concurrent controls Increasing dose (based on TK: AUC/Cmax) Consider unbalanced study design Delimited exposure regime Evaluate pharmacologic action relative to ontogeny of receptors, etc. and
reconcile with modified dosing regime Label and follow-up in birth defects registry
Interpretative Difficulties of Developmental Variations in Experimental Studies
Variability in occurrence of findings
Fate/reversibility studies infrequent
Biologic significance -- extrapolation
High background incidence
Factors Determining Teratogenicity
Chemical and pharmacological propertiesMagnitude and duration of dosageMaternal modulation of dosageAccess to the conceptusDevelopmental stage at time of dosageDisposition within the conceptusSusceptibility of species and individual
There is no single best model. Combinations of these factors determine value of the model.
Regulatory Entities and Concerns
FDA EPA
FDAMA (Pediatrics)
Advocacy Groups
Pharmaceutical Product
Registration
ICH
Food Additives
AnimalHealth
Products
FQPA
TSCATest
Rules
SWDA
Environmental Exposures
FIFRAProduct
Registrations
TradeAssociations
Knowledge of whether condition, agent, procedure, chemical/drug exerts adverse effects on reproduction or development?
What is relative risk to human beings?
Sufficient degree of comfort to enable sound decision-making Guideline studies Additional evaluations Burden of proof is on industry
Reproductive ToxicologyWhat Do the Regulators Want?
Synopsis of Regulatory Assessment Process
Guideline Study
Hazard Identification Data
Animal-Human ConcordanceDevelopmental - High
Reproductive - Less Certain
Regulatory Analysis & Decision
Toxicologist/Regulatory
Regulator
Com
mun
icat
ion
Reproductive Toxicology Is Complicated
Conceptually Dynamic Anatomy & Physiology Interdependence of endpoints Statistics
Litter basedImportance of Historical Controls
• mean
• range
Neurobehavior (potential for latency) Infinite (?) modes of Action
ACE Inhibitors
Dystocia
Logistically Size/design of studies # and diversity of endpoints Decreasing training programs Ease of scoring endpoints
direct effectslatent effects
Cabergoline
DES
Reproductive Toxicology Is Complicated
Selected Differences in Developmental vs. Oncogenic Endpoint Ascertainment
Smaller group sizes (25 vs. minimum 100/group) Macroscopic – histopathology very rare Physical constraints/difficulty Less standardized nomenclature No certification, controls over training, etc.
More impact because earlier in development due to women in clinical trials
Involves coapt organisms (dam & fetuses) Always potential for maternal influence, but goes both ways
Dynamic morphology & function ACE example
Animals evaluated in the midst of changing morphology No two points in development are the same
Exposure hourly and daily key to outcome An important aspect of human studies
Comparison of Study Scale/Size
Major Processes in Mammalian Reproduction
SpermatogenesisOogenesis/ovulationCyclicity (estrous/menstrual)Libido/receptivityConception ImplantationPrenatal developmentParturitionPostnatal development and maturation
Comparative Endocrinology of Menstrual and Estrous Cycles and Early Pregnancy
2816 1612 128 84 4Days from LH Peak
16 20 2412840 12 8 4 0
Human LHFSHE2
P4
Ovulation Ovulation
2 4 6 8 10
Rat
OvulationOvulationand Coitus
PRL
Metestrus Diestrus DiestrusProestrus ProestrusEstrus Metestrus 12
hCG
rCG
A B C D E F
Premating to Conception
Conception to Implantation
Implantation to Closure of Hard Palate
Hard-Palate Closure to End of Pregnancy
Birth to Weaning Weaning to Sexual Maturity
Parturition Litter Size Landmarks of Sexual DevelopmentGestation Length Pup Viability Neurobehavioral Assessment F1 Mating and Fertility Pup Weight Acoustic Startle Response
Organ Weights Motor Activity Learning & Memory
ParturitionGestation Length Pup Viability Litter SizeLandmarks of Sexual Development Pup WeightNeurobehavioral Assessment Organ Weights Acoustic Startle Response F1 Mating and Fertility Motor Activity Hormonal Analyses Learning & Memory Ovarian QuantificationHistopathology Premature Senescence
Postimplantation LossViable FetusesMalformations & VariationsFetal Weight
Postimplantation LossViable FetusesMalformationsVariationsFetal Weight
Estrous Cyclicity Mating Corpora Lutea Fertility Implantation SitesPre-Implantation Loss Spermatogenesis
Estrous CyclicityMatingFertilityCorpora LuteaImplantation SitesPre-Implantation LossSpermatogenesis
Denotes Dosing Period
Standard DART Study Designs
Single- and Multigenerational
Satellite Phase
OECD 415, OECD 416, OPPTS 870.3800, FDA Redbook I, NTP RACB
F1
F2 ????????????????
????????????????
Pre- and Postnatal Development
F1
ICH 4.1.2F0
????????????????
Prenatal DevelopmentICH 4.1.3 OECD 414
OPPTS 870.3600 870.3700
Fertility StudyICH 4.1.12W4W
CMAX
AUC
CMAX
AUC
10W
Endpoints Not Assessed by Current Testing Guidelines
Maternal endocrine profiles Levels of agent in milk, fetus Reproductive events through puberty Reproductive life span Ovarian toxicity (for drugs) Male-mediated effects Postnatal physiology and function apart from
neurobehavior Transplacental carcinogenesis Placental pathology Drug or chemical interaction
Relevancy & Risk Analysis
BiologicDynamics &Dimensions
Integrity of Data Base
Regulators’ Questions
1) was an established, validated model used? 2) was a NOAEL (NOEL) demonstrated? 3) does increasing dose increase severity/incidence?
4) when was the when effect exerted? 5) is the effect reversible? 6) are there indications of sensitization (generational effects or
imprinting)? 7) is the effect gender specific?
8) appropriate TK (AUC/CMAX) comparison between experimental study and estimated human PK or exposure scenarios?
9) are there significant differences in the pattern, timing or magnitude of exposure between guideline studies and human scenarios?
10) is there concordance of effects among species?11) is the mode of action known or deducible?12) is the mechanism of action known?
Extent to Which Guideline Studies Answer Key Regulatory Questions
Fert. P/P DT DT 2-G DNT DT 1-G 2-G Screen DNT4.1.1 4.1.2 4.1.3 3700 3800 6300 414 415 416 421 426
1Validated
Model
2NOAEL
Determined
3Rare Event
w/Dose
4Insult Timing
Elucidated
5 Reversibility
6Imprinting
Phenomenon
7 Gender Basis
8 TK Profiled
9Exposure Mimicked
? ? ? ? ? ? ? ?
10Interspecies
Concordance
11Mode of Action
12Mechanism of
Action
What do regulators want to
know?
OECDEPAICH
(1) Was an Established, Validated Model Used?
Conducted well by trained personnel using sound methodology
Stable experienced staff?
These are not a given and problems occur frequently
For developmental studies rat and rabbit most common
For reproduction, rat alone most common, some use of repro organ data from dog, rabbit and monkey
(2) Was a NOAEL (NOEL) Demonstrated?
Rare events/findings, even if not s.s. may signal treatment-related effect
C D1 D2 D3
0 1 2 1
0 0 0 2
0 2 0 1
Absence of dose response does not fully negate observations
Careful comparison to H.C. mean & range; probably a real signal
Increase dose level and repeat to confirm or refute
Most regulators will rely heavily on concurrent (contemporaneous) control value for comparison
Unbalanced study design may be useful
Total litter loss: In today’s facilities with good care and technical attention 1 or 2 probably constitutes treatment effect
(2) Continued - Was a NOAEL (NOEL) Demonstrated?
Dystocia - similar to above; 1 questionable but 2 or more very likely a real signal. Again not amenable to statistical analysis!
Reduced litter size and early neonatal deaths (< pnd 4) is very sensitive endpoint. May be very low as a mean percentage but deaths exceeding 8/group should be heeded and closely evaluated - may depend on litter size
Live litter size sensitive measure down to mean of 0.5 - 0.75 offspring/litter with n of ~ 30
(2) Continued - Was a NOAEL (NOEL) Demonstrated?
(3) Does Increasing Dose IncreaseSeverity/Incidence?
Increases in no. of litters affected
Increases in no. of fetuses/progeny affected/litter
These represent signals of enhanced concern
(4) When Was the When Effect Exerted?
Single or multiple exposures required; need to identify timing of insult
Very important for further study of developmental effects; shorten study effort, etc.
In reproductive studies can greatly benefit evaluative process by identifying mode of action
Pre-ovulatory LH surge in rats, validity to human reproduction and differention between central or peripheral sites of action
(5) Is the Effect Reversible?
Was full recovery demonstrated
Reduced fetal weight in D.T.; clarify increased postnatal loss in repro-phase
High dose, MTD, clarifications
However, remember that disrupted schedule of development may have consequences later in life especially for neurobehavioral measures
(6) Are There Indications of Sensitization(Generational Effects or Imprinting)?
In 2-generation studies remember: a decreased response in later generations may be result of loss of sensitive F0/F1 individuals (selection)
An increased response in F1 or F2 may represent sensitization unless bioaccumulation is demonstrated
(7) Is the Effect Gender Specific?
Designates population at risk
Often can be deduced from organ histopathology or other measures
With agents not producing overt toxic signs discerning gender basis not always straightforward
Gives guidance to possible mode of action
In 2-generation studies, may need to do additional mating to untreated males or females
(8) Appropriate TK (AUC/CMAX) ComparisonBetween Experimental Study and EstimatedHuman PK or Exposure Scenarios (i.e., MHRD)
Key for: Standardizing “internal dose” or exposure
Comparing interspecies concordance for determining differences in biologic sensitivity
Establishing bioavailability
Discerning dose-dependent PK or changes in metabolism over course of exposure
(9) Are There Significant Differences in the Pattern, Timing or Magnitude of Exposure Between Guideline Studies and Human Scenarios?
Is product use such that human exposure may be very brief (hrs.) or intermittent. PBPK model useful here for reproduction
For developmental studies, no point in developmental time is the same, so abbreviated exposures (i.e., 1 hr/day) not acceptable?
Children’s dietary intake different in make-up, and changes with age.
Children’s GFRs much greater than adult & decrease with maturity
(10) Is There Concordance of Effects Among Species?
If so, there is enhanced concern, in its absence no diminished concern
Greater the number of species stronger the signal
TK should be used to compare internal exposures
Ensure that design/statistical power is comparable between different studies (species) prior to declaring nonconcordance
(11) Is the Mode of Action Known or Deducible?
Key for the discipline’s “learning curve” and refinement of risk assessment process
Because in-utero studies involved coapt organisms role of maternal toxicity may be crucial especially at exaggerated doses
Discerning mode of action very useful in understanding effects occurring during lactation
(12) Is the Mechanism of Action Known?
Very difficult and not fully illuminated for known developmental toxicants
Few reproductive toxicants well studied
Key for the discipline’s learning curve and refinement of risk assessment process
Comparison of Prenataland Postnatal Toxicity Profiles
Toxicity
Log of Dose
MaternalMaternal
DevelopmentalDevelopmental
Prenatal – valid and insightful – Embryonic exposure – Mode of action
Postnatal – valid only – when xenobiotic level is measured in both mother and
offspring
Relationship Between Developmentand Phenotypic Diversity
Phenotypic Expression
and Diversity
Time in Development (Age)
EmbryonicPeriod
EmbryonicPeriod
FetalPeriodFetal
PeriodPostnatal
PeriodPostnatal
Period
Extent of Differentiation
BirthBirth
Effects on Prenatal and Postnatal Development Including Maternal Function
ICH 4.1.2 (Segment III)
Denotes Treatment Period
GD 6 PND 20
Gestation Lactation
Weaning Growth Mating GestationPN day 21 9 wks 2 wks 3 wks
F1
F2
Female (Rat)
(Macroscopic Pathology)
PN day 17 PN day 80
Behavioral/Anatomic Measures
Motor ActivityAuditory StartleWater MazeDevelopmental Landmark
Vaginal PatencyPreputial Separation
Denotes Possible Transfer Via Milk
Comparison of Prenatal and Postnatal Modes of Exposure
Drug Transfer to Offspring
Drug Levels in Offspring
Maternal Blood vs.Offspring Levels
Exposure Route toOffspring
Commentary
Prenatal
Nearly all transferred
Cmax and AUC measured
Maternal often a surrogate
Modulated IV exposure, via placenta
Timing of exposure is critical
Postnatal
Apparent selectivity (“barrier”)
Not routinely measured
Maternal levels probably NOT a good predictor
Oral, via immature GI tract
Extent of transfer to milk and neonatal bioavailability is key to differentiating indirect (maternal) effectsfrom neonatal sensitivity
Prenatal Treatment Postnatal
Embryo/Fetus Placenta Mother Mammae Neonate
Organogenesis (classically defined) is unaffected
Effects are severe
Risk is low
Caused by ACEinh that cross placenta
ACEinhFetal
Hypotension
RenalCompromise
(Anuria)Oligohydramnios
Calvarial Hypoplasia
Neonatal Anuria
IUGR
Death
Case Study: Functional Alteration Example ACE Inhibition-Induced Fetopathy (Human)
Case Study: Functional Alteration Example
ACE Inhibition in Developing Rats
RAS (renin-angiotensin system) begins GD17
No ‘apparent’ effect in initial reproductive studies Nonstatistically significant increase in postnatal mortality (~8%)
Subsequent postnatal studies with direct administration to pups Growth retardation
Renal alterations (anatomic and functional)
Mortality increased to more than 30%
Selective Juvenile Toxicity of Quinilones
Drug
Ofloxacin (and other quinilones)
Modified from Stahlmann et al., 1997.
Species &Treatment
Multiple species,postnatal exposure.20 mg/kg (dog, 3 mo.)600 mg/kg (rat, 5 wk)
Effects
Chondrotoxic effects. Cartilage erosion in weight-bearing joints.
Gait alterations in juvenile dogs only.
Remarks
Human relevance unknown; drugs contraindicated in juvenile patients.
Mechanism: Probable deficiency of bioavailable Mg2+ in cartilage (quinilones chelate divalent cations).
No effect in routine segment III studies.
Reasons for Apparent Failed Predictions
Appropriate studies not conducted Incidence of effect too low for experimental
detectionUnknown/unstudied type(s) of effectHypersensitive individuals in human population Interaction of multiple agentsUnfounded/nonexistent claims or effectsHuman exposure is overestimated by
experimental design