1. National Institute of Child Health and Human Development
Workshop on Extrapolation of Non-clinical Models to Pediatric Clinical Studies:
Setting the Research Agenda

2. S Contributors Tracy S. Zoetis, M.S. Amy L. Lavin, Ph.D.
(Now with Milestone)
Amy L. Lavin, Ph.D.
Michael J. Yang
Joseph F. Holson, Ph.D. S

3. Prenatal Models, Ontogeny, and Postnatal Life

4. Conceptual Roadmap of Embryonic Development
Cellular Potency
Cellular
Differentiation
DeSesso, 1997

5. Gestational Milestones for MammalsB C D E
Primitive Early Organogenesis Usual Species Implantation Streak Differentiation Ends Parturition
Rat
Mouse
Rabbit
Hamster
Guinea Pig ~
Monkey ~
Human ~
1In gestational days; day of confirmed mating = gestational day 0
2Letters refer to positions on Figure 4 (Conceptual Roadmap of Embryonic Development)
DeSesso, 1997

6. Ontogeny Recapitulates Phylogeny (von Baer, 1828)
General features appear earlier in embryos than do specialized features
Embryos of higher animals pass through stages that are similar to those of embryos of lower species

7. Ontogeny Recapitulates Phylogeny

8. Why should we be interested in organ system maturation?

9. Why should we be interested in organ system maturation?
It is essential for comparing postnatal toxicity among species

10. Concept of Physiologic Time

11. Concept of Physiologic Time
Comparisons among Species
Comparisons among Developmental Stages

12. Maturational Data for Various Species
Syrian
Hamster
Guinea
Pig
Rhesus
Monkey
Human
Mouse
Rat
Rabbit
Gestation
(days)
267 16 20 22 32 63
167
Minimal
Breeding
Age
(weeks) 5
6.5 28 32 4 10
728 7
10.5
218
Human to
Animal
Life Span
1.0 66 44 33 12 17
4.4

13. Physiologic Time
A method for scaling the lifespan of different species so that comparable stages of maturation are congruent, regardless of chronological age

14. Time to Develop Adult Characteristics
100
Rat
Human %
Adult Status 5 10 15 20
Age (years)

15. Relationship Between Extent of Maturation and Birth in Rats and Humans
100%
Adult Status
= Birth
Maturation
Human
Rat
Conception
Physiologic Time

16. Difficulties in a priori Selection
of Models for Preclinical Pediatric Toxicity

17. Relationship Between Development and Phenotypic Diversity
Extent of Differentiation
Embryonic
Period
Fetal
Period
Postnatal
Period
Degree of Phenotypic Variability
Birth
Time in Development (Age)

18. Pulmonary System

19. Human Fetal and Postnatal Lung Development

20. Developmental Stages - Morphology
Embryonic Stage
(Gestational Days 33-37)
Pseudoglandular Stage
(Gestational Week 13)
Canalicular Stage
(Gestational Week 20)
Saccular Stage
(Gestational Week 34)
Alveolar Stage
(2 weeks of age)

21. Interspecies Comparison of Alveolar Development
Species Onset At Birth Critical Period Completion
Human GWK36 Beginning Birth - 2 years 6-8 years
Dog ? Beginning weeks 16 weeks
Monkey ? Completed in utero Birth
Rat PND4 Not Started days 3 weeks
Rabbit ? Beginning ? 6 weeks
Ferret ? Not Started ? 6 months
Mouse PND4 Not Started days 3 weeks
Modified from Zoetis, 1999

22. Conclusions - Lung
Pulmonary development occurs in stages that span prenatal and postnatal periods
Stages are similar in humans and animals
Timing of stages differs between species
Species differ with regard to lung maturity at birth

23. Conclusions - Lung
Pulmonary development occurs in stages that span prenatal and postnatal periods
Stages are similar in humans and animals
Timing of stages differs between species
Species differ with regard to lung maturity at birth
Timing of alveolar development is the critical factor in species selection for models of the human pediatric lung

24. Cardiac System

25. Comparison of Perinatal Status of Cardiac Structure & Function in Humans & Rats
Parameter Humans Rats
Relative Heart Weight Constant Decreasing
Coronary Circulation Major branches established Major branches of coronary
at birth arteries develop during
first 2 weeks after birth
Cardiac Myocytes Increase in number & size Increase in number & size
Autonomic Innervation Established & functional Becomes established &
at birth matures functionally during
T-tubule System Functional at birth Formed during first 2 weeks
after birth
Heart Rate Decreasing Increasing through first week,
decreasing beginning in
second week

26. Conclusions - Heart
Key features of perinatal cardiac microstructure and function have not been studied in sufficient depth to assess interspecies concordance. For example,
Establishment of autonomic innervation
Status of sarcoplasmic reticulum and
T-tubule system
Stage for development of coronary circulation
Ontogeny of heart rate

27. Conclusions - Heart
Because new pharmaceuticals or other chemicals may interfere with various aspects of perinatal heart development, selection of appropriate animal models can only be accomplished by establishing concordance between the developmental stages in animals and pediatric patients.

28. Current Models and Safety Test Designs
Challenges Regarding
Current Models and Safety Test Designs

29. Pediatric Classifications
12 to <16 Years
Adolescents
2 to 12 years
Children
1 month to 2 years
Infants
Birth to 1 month
Neonates

30. Non-Human Developmental Classifications
14-26
36-48
20-28
35-60
Adolescent
4-14
6-36
6-20
21-35
Child
2-4
0.5-6
3-6
10-21
Infant
<2
<0.5
<3
<10
Neonate
Mini-Pig (wks)
Primate (mos)
Dog (wks)
Rat (days)
Category

31. Non-Human Developmental Classifications
14-26
36-48
20-28
35-60
Adolescent
4-14
6-36
6-20
21-35
Child
2-4
0.5-6
3-6
10-21
Infant
<2
<0.5
<3
<10
Neonate
Mini-Pig (wks)
Primate (mos)
Dog (wks)
Rat (days)
Category

32. Similarity of Age Should Be Measured in Physiologic Time
Comparable categories for ages of various animal species are dependent on the anatomical and functional status of individual organs or systems

33. Conclusions Parallelism exists among species regardless of lifespan
Animal models are predictive only if they mimic the human situation that is of interest
Anatomical stages, when important
State of physiological or functional maturation
Concept of similarity in physiologic time
Additional measurements and changes to current guidelines could increase our ability to predict postnatal toxicity