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From Neonates to adolescents

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From Neonates to adolescents
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
Historical background
•
•
•
•
•
Sulfanilamide
Sulfisoxazole
Chloramphenicol
Thalidomide
Diethylstilbestrol (DES)
©K. Hoppu 4.4.2008
1937
1954
1958
1961
1971
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©K. Hoppu 4.4.2008
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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 1956;18:614-25.
©K. Hoppu 4.4.2008
3
Burns L, Hodgman J, Cass A. fatal circulatory collapse in premature infants receiving chloramphenicol.
New England Journal of Medicine 1959;261(26):1318-21.
©K. Hoppu 4.4.2008
4
Children = small adults
=
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Major Developmental Periods
• Prenatal development / prematurity
• Birth - Rapid postnatal development
• Prepuberty
• Puberty
• Postpubertal adolescence
Growth and development – a continuum
©K. Hoppu 4.4.2008
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Variations in the pattern of pubertal
changes in girls
©K. Hoppu 4.4.2008
Marshall WA, Tanner JM. Arch Dis Child 1969;44(235):291-303.
9
Variations in the pattern of pubertal
changes in boys
©K. Hoppu 4.4.2008
Marshall WA, Tanner JM. Arch Dis Child 1970;45(239):13-23
10
Effects of growth and development on:
• Dosing
• Size
• Pharmacokinetics – ADME
• Need for special formulations
• Adverse effects
• Efficacy
©K. Hoppu 4.4.2008
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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
©K. Hoppu 4.4.2008
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Pharmacokinetics - Absorption
• Bioavailability
• Special formulations
• Developmental differences?
• Effects of food
• Systemic absorption of topical
preparations
©K. Hoppu 4.4.2008
13
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):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 2003;349(12):1157-67.
©K. Hoppu 4.4.2008
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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
©K. Hoppu 4.4.2008
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Pharmacokinetics - Distribution
• Body compartments and G&D
• Protein binding
• Bilirubin displacement
• Permeability of BBB
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©K. Hoppu 4.4.2008
From: Kearns GL et al. N Engl J Med 2003;349(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
No metabolism
©K. Hoppu 4.4.2008
With metabolism
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©K. Hoppu 4.4.2008
From: Kearns GL et al. N Engl J Med 2003;349(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
©K. Hoppu 4.4.2008
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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 2003;349(12):1157-67.
©K. Hoppu 4.4.2008
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Age-associated Changes in Ceftriaxone
Pharmacokinetics
20
2
15
1,5
10
1
5
0,5
0
0
1-8d
9-30d
1-12m
1-6y
18-49y
50-74y
CL (ml/min; ml/min/kg)
CL (ml/min/m 2)
CL (ml/min)
CL (ml/min/m2)
Cl (ml/min/kg)
75-92y
Age
©K. Hoppu 4.4.2008
From: Hayton WL, Stoeckel K. Clin Pharmacokin 1986;11:76-86
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Age-associated Changes in Ceftriaxone
Pharmacokinetics
20
T/2 (h)
15
10
5
0
1-8d
9-30d
1-12m
1-6y
18-49y
50-74y
75-92y
Age
©K. Hoppu 4.4.2008
From: Hayton WL, Stoeckel K. Clin Pharmacokin 1986;11:76-86
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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
©K. Hoppu 4.4.2008
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Theophylline Clearance and Pubertal
Development
©K. Hoppu 4.4.2008
Kolski GB ym. AJDC 1987; 141: 282-7
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Efficacy of medicinal products in
the paediatric population
• Effect of G&D on efficacy
• PG-inhibitors and PDA
©K. Hoppu 4.4.2008
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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 4.4.2008
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Adverse effects specific to the
paediatric population
• Corticosteroids
• Tetracyclines
• Discoloration of teeth
• ASA
• Reye -syndrome
• Quinolones
• Disturbed cartilage growth
©K. Hoppu 4.4.2008
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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
©K. Hoppu 4.4.2008
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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 4.4.2008
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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?*
©K. Hoppu 4.4.2008
*CHMP Guideline On Clinical Trials In Small Populations (www.emea.eu.int)
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