from neonates to adolescents
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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From neonates to adolescentsFrom neonates to adolescents
Kalle Hoppu MD, PhDDirector, 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
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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Historical backgroundHistorical background
Sulfanilamide 1937
Sulfisoxazole 1954
Chloramphenicol 1958
Thalidomide 1961
Diethylstilbestrol (DES) 1971
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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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.
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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Children = small adultsChildren = small adults
==
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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Growth & DevelopmentGrowth & Development
Growth and development – a continuumGrowth and development – a continuum
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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Major Developmental PeriodsMajor Developmental Periods
Prenatal development / prematurity
Birth - Rapid postnatal development
Prepuberty
Puberty
Postpubertal adolescence
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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Variations in the pattern of pubertal changes in girls
Variations in the pattern of pubertal changes in girls
Marshall WA, Tanner JM. Arch Dis Child 1969;44(235):291-303.
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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Variations in the pattern of pubertal changes in boys
Variations in the pattern of pubertal changes in boys
Marshall WA, Tanner JM. Arch Dis Child 1970;45(239):13-23
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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Effects of growth and development on:Effects of growth and development on:
Dosing– Size
– Pharmacokinetics – ADME
– Need for special formulations
Adverse effects
Efficacy
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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Smaller size
– Smaller absolute dose
Dose relative to size
– mg/kg
– mg/m2
– mg/kg3/4 (allometric)
Large body surface area to mass ratio
Size related issues in dosingSize related issues in dosing
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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Pharmacokinetics - AbsorptionPharmacokinetics - Absorption
Bioavailability– Special formulations
– Developmental differences?
Effects of food
Systemic absorption of topical preparations
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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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.
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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Pharmacokinetics - GI AbsorptionPharmacokinetics - GI Absorption
Physiology– Higher intragastric pH in newborns– Gastric emptying and intestinal mobility matures during first
weeks of life
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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From: Kearns GL et al. N Engl J Med 2003;349(12):1157-67.
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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Pharmacokinetics - Percutaneous Absorption
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...
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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Pharmacokinetics - DistributionPharmacokinetics - Distribution
Body compartments and G&D
Protein binding
Bilirubin displacement
Permeability of BBB
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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From: Kearns GL et al. N Engl J Med 2003;349(12):1157-67.
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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Pharmacokinetics - EliminationPharmacokinetics - Elimination
Metabolism– Postnatal development
– Toddler peak
– Pubertal slowing
– Qualitative differences
Renal elimination
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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With metabolism
No metabolism
Effects of Fetal Drug MetabolismEffects of Fetal Drug Metabolism
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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From: Kearns GL et al. N Engl J Med 2003;349(12):1157-67.
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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Pharmacokinetics - Renal EliminationPharmacokinetics - Renal Elimination
Adaptation after birth
High renal elimination capacity in young children
Return to adult capacity level with pubertal development
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.
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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Age-associated Changes in Ceftriaxone Pharmacokinetics
Age-associated Changes in Ceftriaxone Pharmacokinetics
0
5
10
15
20
1-8d 9-30d 1-12m 1-6y 18-49y 50-74y 75-92y
Age
CL
(m
l/m
in/m
2)
0
0.5
1
1.5
2
CL
(m
l/m
in;
ml/
min
/kg
)
( CL)ml/min
( CL)ml/min/m2
( Cl)ml/min/kg
From: Hayton WL, Stoeckel K. Clin Pharmacokin 1986;11:76-86
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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Age-associated Changes in Ceftriaxone Pharmacokinetics
Age-associated Changes in Ceftriaxone Pharmacokinetics
0
5
10
15
20
1-8d 9-30d 1-12m 1-6y 18-49y 50-74y 75-92y
Age
T/2
(h
)
From: Hayton WL, Stoeckel K. Clin Pharmacokin 1986;11:76-86
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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Variation in PharmacokineticsVariation 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
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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Theophylline Clearance and Pubertal Development
Theophylline Clearance and Pubertal Development
Kolski GB ym. AJDC 1987; 141: 282-7
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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Efficacy of medicinal products in the paediatric population
Efficacy of medicinal products in the paediatric population
Effect of G&D on efficacy– PG-inhibitors
and PDA
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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Adverse effects specific to the paediatric population
Adverse effects specific to the paediatric population
Corticosteroids
Tetracyclines– Discoloration of teeth
ASA– Reye -syndrome
Quinolones– Disturbed cartilage growth
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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Safety studies in childrenSafety 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
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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When are studies on efficacy of medicinal products needed in the paediatric population?
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
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
36 |*CHMP Guideline On Clinical Trials In Small Populations (www.emea.eu.int)
Clinical trials to demonstrate efficacy/safety in children must be
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?*
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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Is it ethical to perform paediatri
c drug research
?
Is it ethical not to
perform paediatric
drug research?
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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Characteristics of clinical trials/research in children
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
Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007
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Characteristics of clinical trials/research in children...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