Transcript From neonates to adolescents

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
Vice-chairman, CHMP-Paediatric Working Party (PEG) at the EMEA
Chairman, Sub-Committee for Paediatric Clinical Pharmacology,
IUPHAR, Division of Clinical Pharmacology
Historical background
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Sulfanilamide
Sulfisoxazole
Chloramphenicol
Thalidomide
Diethylstilbestrol (DES)
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1937
1954
1958
1961
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 1956;18:614-25.
Burns L, Hodgman J, Cass A. fatal circulatory collapse in premature infants receiving chloramphenicol.
New England Journal of Medicine 1959;261(26):1318-21.
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
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Marshall WA, Tanner JM. Arch Dis Child 1969;44(235):291-303.
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Variations in the pattern of pubertal changes
in boys
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Marshall WA, Tanner JM. Arch Dis Child 1970;45(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
• 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 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.
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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 G&D
• Protein binding
• Bilirubin displacement
• Permeability of BBB
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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
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With metabolism
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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
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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.
Age-associated Changes in Ceftriaxone
Pharmacokinetics
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15
1,5
10
1
5
0,5
0
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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
From: Hayton WL, Stoeckel K. Clin Pharmacokin 1986;11:76-86
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Age-associated Changes in Ceftriaxone
Pharmacokinetics
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T/2 (h)
15
10
5
0
1-8d
9-30d
1-12m
1-6y
18-49y
50-74y
75-92y
Age
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
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Theophylline Clearance and Pubertal
Development
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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
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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 G&D 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?*
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*CHMP Guideline On Clinical Trials In Small Populations (www.emea.eu.int)
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Is it ethical
to perform
paediatric
drug
research?
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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 benefit:risk 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. sizerelated issues
• Capability to cooperate etc.
developmental issues
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