From neonates to adolescents

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From neonates to adolescents

• Kalle Hoppu MD, PhD
• 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

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Historical background

• Sulfanilamide 1937
• Sulfisoxazole 1954
• Chloramphenicol 1958
• Thalidomide 1961
• Diethylstilbestrol (DES) 1971

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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 195618614-25.
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Burns L, Hodgman J, Cass A. fatal circulatory
collapse in premature infants receiving
chloramphenicol. New England Journal of Medicine
1959261(26)1318-21.
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Children small adults

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Growth Development
Growth and development a continuum
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Major Developmental Periods

• Prenatal development / prematurity
• Birth - Rapid postnatal development
• Prepuberty
• Puberty
• Postpubertal adolescence

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Variations in the pattern of pubertal changes in
girls
Marshall WA, Tanner JM. Arch Dis Child
196944(235)291-303.
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Variations in the pattern of pubertal changes in
boys
Marshall WA, Tanner JM. Arch Dis Child
197045(239)13-23
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Effects of growth and development on

• Dosing
• Size
• Pharmacokinetics ADME
• Need for special formulations
• Adverse effects
• Efficacy

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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

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Pharmacokinetics - Absorption

• Bioavailability
• Special formulations
• Developmental differences?
• Effects of food
• Systemic absorption of topical preparations

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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
2003349(12)1157-67.
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Pharmacokinetics - GI Absorption

• Physiology
• Higher intragastric pH in newborns
• Gastric emptying and intestinal mobility matures
  during first weeks of life

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From Kearns GL et al. N Engl J Med
2003349(12)1157-67.
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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...

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Pharmacokinetics - Distribution

• Body compartments and GD
• Protein binding
• Bilirubin displacement
• Permeability of BBB

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From Kearns GL et al. N Engl J Med
2003349(12)1157-67.
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Pharmacokinetics - Elimination

• Metabolism
• Postnatal development
• Toddler peak
• Pubertal slowing
• Qualitative differences
• Renal elimination

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Effects of Fetal Drug Metabolism
With metabolism
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From Kearns GL et al. N Engl J Med
2003349(12)1157-67.
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Pharmacokinetics - Renal Elimination

• Adaptation after birth
• High renal elimination capacity in young children
• Return to adult capacity level with pubertal
  development

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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
2003349(12)1157-67.
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Age-associated Changes in Ceftriaxone
Pharmacokinetics
From Hayton WL, Stoeckel K. Clin Pharmacokin
19861176-86
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Age-associated Changes in Ceftriaxone
Pharmacokinetics
From Hayton WL, Stoeckel K. Clin Pharmacokin
19861176-86
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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

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Theophylline Clearance and Pubertal Development
Kolski GB ym. AJDC 1987 141 282-7
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Efficacy of medicinal products in the paediatric
population

• Effect of GD on efficacy
• PG-inhibitors and PDA

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Adverse effects specific to the paediatric
population

• Corticosteroids
• Tetracyclines
• Discoloration of teeth
• ASA
• Reye -syndrome
• Quinolones
• Disturbed cartilage growth

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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

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When are studies on efficacy of medicinal
products needed in the paediatric population?

• Effect of GD on efficacy to be suspected
• Antidepressants
• Exclusively paediatric diseases
• Problems of premature birth
• Febrile convulsions
• Paediatric forms of diseases
• Recurrent AOM
• ALL

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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?

CHMP Guideline On Clinical Trials In Small
Populations (www.emea.eu.int)
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Is it ethical to perform paediatric drug research?
Is it ethical not to perform paediatric drug
research?
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Characteristics of clinical trials/research in
children

• Ethics
• General obligation to protect minors
• Acceptable benefitrisk ratio
• In addition Minimal harm
• Children incapable of giving legal consent
• Opinion of the minor to be taken into
  consideration
• Ethics Committee approval
• Paediatric expertise
• In the Committee
• External advice used

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Characteristics of clinical trials/research in
children...

• Scientifically valid design
• Assessment of effects with methods validated for
  the age group
• Power to be able to answer the question
• Technical problems
• Limited sample volumes etc. size-related issues
• Capability to cooperate etc. developmental issues

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