Transcript Why do we need special drug development for children?

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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2007
Historical background
 Sulfanilamide
1937
 Sulfisoxazole
1954
 Chloramphenicol
1958
 Thalidomide
 Diethylstilbestrol (DES)
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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
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
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 (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 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
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
20
2
15
1.5
10
1
5
0.5
0
0
1-8d
9-30d
1-12m
1-6y
18-49y
50-74y
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From: Hayton WL, Stoeckel K. Clin Pharmacokin 1986;11:76-86
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75-92y
CL (ml/min; ml/min/kg)
CL (ml/min/m2)
)CL (ml/min
)CL (ml/min/m2
)Cl (ml/min/kg
Age-associated Changes in Ceftriaxone
Pharmacokinetics
20
T/2 (h)
15
10
5
0
1-8d
9-30d
1-12m
1-6y
Age
18-49y
50-74y
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From: Hayton WL, Stoeckel K. Clin Pharmacokin 1986;11:76-86
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75-92y
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
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)
Is it
ethical to
perform
paediatric
drug
research?
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Is it ethical
not to
perform
paediatric
drug
research?
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. size-related issues
– Capability to cooperate etc. developmental issues
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2007