0. From neonates to adolescents
Kalle Hoppu, M.D., Ph.D.
Director, Poison Information Centre, Helsinki University Central Hospital
Docent (Ass. professor) Dept.s of Paediatrics and Clinical Pharmacology, University of Helsinki, Helsinki, Finland
Chairman, Sub-Committee for Paediatric Clinical Pharmacology, IUPHAR, Division of Clinical Pharmacology
Member, WHO Expert Advisory Panel on Drug Evaluation
Director FINPEDMED - Finnish Investigators Network for Pediatric Medicines

1. Historical background
Sulfanilamide
Sulfisoxazole
Chloramphenicol
Thalidomide
Diethylstilbestrol (DES) 1971
©K. Hoppu

2. ©K. Hoppu

3. Silverman W, Andersen D, Blanc W, Crozier D
Silverman W, Andersen D, Blanc W, Crozier D. A difference in mortality rate and incidence of kernicterus among premature infants allotted to two prophylactic antibacterial regimens. Pediatrics 1956;18:
©K. Hoppu

4. Burns L, Hodgman J, Cass A. fatal circulatory collapse in premature infants receiving chloramphenicol. New England Journal of Medicine 1959;261(26):
©K. Hoppu

5. Children = small adults
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8. Major Developmental Periods
Prenatal development / prematurity
Birth - Rapid postnatal development
Prepuberty
Puberty
Postpubertal adolescence
Growth and development – a continuum
©K. Hoppu

9. Variations in the pattern of pubertal changes in girls
©K. Hoppu
Marshall WA, Tanner JM. Arch Dis Child 1969;44(235):

10. Variations in the pattern of pubertal changes in boys
©K. Hoppu
Marshall WA, Tanner JM. Arch Dis Child 1970;45(239):13-23

11. Effects of growth and development on:
Dosing
Size
Pharmacokinetics – ADME
Need for special formulations
Adverse effects
Efficacy
©K. Hoppu

12. Size related issues in dosing
Smaller size
Smaller absolute dose
Dose relative to size
mg/kg
mg/m2
mg/kg3/4 (allometric)
Large body surface area to mass ratio
©K. Hoppu

13. Pharmacokinetics - Absorption
Bioavailability
Special formulations
Developmental differences?
Effects of food
Systemic absorption of topical preparations
©K. Hoppu

14. From: Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology- -drug disposition, action, and therapy in infants and children. N Engl J Med 2003;349(12):
©K. Hoppu

15. Pharmacokinetics - GI Absorption
Physiology
Higher intragastric pH in newborns
Gastric emptying and intestinal mobility matures during first weeks of life
©K. Hoppu

16. From: Kearns GL et al. N Engl J Med 2003;349(12):1157-67.
©K. Hoppu
From: Kearns GL et al. N Engl J Med 2003;349(12):

17. Pharmacokinetics - Percutaneous Absorption
Physiology
Increased percutaneous absorption
Total BSA/BW larger in newborns and infants
Systemic exposure (in mg/kg) increased
Examples of substances causing toxicity through percutaneous absoprtion
Aniline, naphtalene, phenol, salisylic acid, corticosteroids, hexachlorophen
©K. Hoppu

18. Pharmacokinetics - Distribution
Body compartments and G&D
Protein binding
Bilirubin displacement
Permeability of BBB
©K. Hoppu

19. From: Kearns GL et al. N Engl J Med 2003;349(12):1157-67.
©K. Hoppu
From: Kearns GL et al. N Engl J Med 2003;349(12):

20. Pharmacokinetics - Elimination
Metabolism
Postnatal development
Toddler peak
Pubertal slowing
Qualitative differences
Renal elimination
©K. Hoppu

21. Effects of Fetal Drug Metabolism
No metabolism
With metabolism
©K. Hoppu

22. From: Kearns GL et al. N Engl J Med 2003;349(12):1157-67.
©K. Hoppu
From: Kearns GL et al. N Engl J Med 2003;349(12):

23. Pharmacokinetics - Renal Elimination
Adaptation after birth
High renal elimination capacity in young children
Return to adult capacity level with pubertal development
©K. Hoppu

24. From: Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology- -drug disposition, action, and therapy in infants and children. N Engl J Med 2003;349(12):
©K. Hoppu

25. Age-associated Changes in Ceftriaxone Pharmacokinetics
©K. Hoppu
From: Hayton WL, Stoeckel K. Clin Pharmacokin 1986;11:76-86

26. Age-associated Changes in Ceftriaxone Pharmacokinetics
©K. Hoppu
From: Hayton WL, Stoeckel K. Clin Pharmacokin 1986;11:76-86

27. Variation in Pharmacokinetics
Adults and children
Interindividual variation
Genetics, environmental factors etc.
Intraindividual variation
Disease, concomitant medication etc.
Children
Variation caused by development
Varying velocity of development
©K. Hoppu

28. Theophylline Clearance and Pubertal Development
©K. Hoppu
Kolski GB ym. AJDC 1987; 141: 282-7

29. Efficacy of medicinal products in the paediatric population
Effect of G&D on efficacy
PG-inhibitors and PDA
©K. Hoppu

30. Patent ductus arteriosus (PDA)
EUDIPHARM 6th European Course
Evaluation of Medicinal Products in Children
Patent ductus arteriosus (PDA)
Allows 90% of RV output to bypass high-resistance pulmonary vascular bed in utero
Postnatally, starts to close within first few hours after birth
In term infant closure usually complete by 72 h
©K. Hoppu
©K. Hoppu

31. Adverse effects specific to the paediatric population
Corticosteroids
Tetracyclines
Discoloration of teeth
ASA
Reye -syndrome
Quinolones
Disturbed cartilage growth
©K. Hoppu

32. Safety studies in children
A larger number of study subjects are needed for assessment of safety than for efficacy
Effects on growth and development can only be confirmed in paediatric studies
Studies require long term follow-up
Confirmation of safety signals from
Juvenile animal studies
Off-label use
©K. Hoppu

33. Effect of G&D on efficacy to be suspected Antidepressants
When are studies on efficacy of medicinal products needed in the paediatric population?
Effect of G&D on efficacy to be suspected
Antidepressants
Exclusively paediatric diseases
Problems of premature birth
Febrile convulsions
Paediatric forms of diseases
Recurrent AOM
ALL
©K. Hoppu

34. Clinical trials to demonstrate efficacy/safety in children must be
Ethically acceptable
Designed to answer the question
Meaningful, age appropriate outcomes
Control treatment
Placebo/unlicensed current treatment?
Using validated methods for assessment of effects
Validated in age groups to be studied
Powered to be able to answer the question
Appropriate design for small populations?*
©K. Hoppu
*CHMP Guideline On Clinical Trials In Small Populations (