From neonates to adolescents Kalle Hoppu, M.D., Ph.D. Director, Poison Information Centre, Helsinki University Central Hospital Docent (Ass. professor)

From neonates to From neonates to adolescentsadolescents

Kalle Hoppu, M.D., Ph.D.Kalle Hoppu, M.D., Ph.D.Director, Poison Information Centre, Helsinki University Central HospitalDirector, Poison Information Centre, Helsinki University Central Hospital

Docent (Ass. professor) Dept.s of Paediatrics and Clinical Pharmacology, Docent (Ass. professor) Dept.s of Paediatrics and Clinical Pharmacology, University of Helsinki, Helsinki, FinlandUniversity of Helsinki, Helsinki, Finland

Chairman, Sub-Committee for Paediatric Clinical Pharmacology, Chairman, Sub-Committee for Paediatric Clinical Pharmacology, IUPHAR, Division of Clinical PharmacologyIUPHAR, Division of Clinical Pharmacology

Member, WHO Expert Advisory Panel on Drug EvaluationMember, WHO Expert Advisory Panel on Drug Evaluation

DirectorDirector FINPEDMEDFINPEDMED - Finnish Investigators Network for Pediatric Medicines - Finnish Investigators Network for Pediatric Medicines

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Historical backgroundHistorical 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 1956;18:614-25.©K. Hoppu 4.4.2008 4

Burns L, Hodgman J, Cass A. fatal circulatory collapse in premature infants receiving chloramphenicol. New England Journal of Medicine 1959;261(26):1318-21.

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Children = small adultsChildren = small adults

==

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Major Developmental PeriodsMajor Developmental Periods

• Prenatal development / prematurity

• Birth - Rapid postnatal development

• Prepuberty

• Puberty

• Postpubertal adolescenceGrowth and development – a continuum

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Variations in the pattern of pubertal Variations in the pattern of pubertal changes in girlschanges in girls

Marshall WA, Tanner JM. Arch Dis Child 1969;44(235):291-303.

11©K. Hoppu 4.4.2008 Marshall WA, Tanner JM. Arch Dis Child 1970;45(239):13-23

Variations in the pattern of pubertal Variations in the pattern of pubertal changes in boyschanges in boys

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Effects of growth and development Effects of growth and development on:on:

• Dosing

• Size

• Pharmacokinetics – ADME

• Need for special formulations

• Adverse effects

• Efficacy

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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

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Pharmacokinetics - AbsorptionPharmacokinetics - 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 Pharmacokinetics - GI AbsorptionAbsorption

• Physiology

• Higher intragastric pH in newborns

• Gastric emptying and intestinal mobility matures during first weeks of life

©K. Hoppu 4.4.2008 17From: Kearns GL et al. N Engl J Med

2003;349(12):1157-67.

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Pharmacokinetics - Pharmacokinetics - Percutaneous AbsorptionPercutaneous 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 - DistributionPharmacokinetics - Distribution

• Body compartments and G&D

• Protein binding

• Bilirubin displacement

• Permeability of BBB

©K. Hoppu 4.4.2008 20From: Kearns GL et al. N Engl J Med 2003;349(12):1157-67.

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Pharmacokinetics - EliminationPharmacokinetics - Elimination

• Metabolism

• Postnatal development

• Toddler peak

• Pubertal slowing

• Qualitative differences

• Renal elimination

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With metabolism

No metabolism

Effects of Fetal Drug MetabolismEffects of Fetal Drug Metabolism

23©K. Hoppu 4.4.2008From: Kearns GL et al. N Engl J Med 2003;349(12):1157-67.

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Pharmacokinetics - Renal Pharmacokinetics - Renal EliminationElimination

• 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.©K. Hoppu 4.4.2008 25

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Age-associated Changes in Ceftriaxone Age-associated Changes in Ceftriaxone PharmacokineticsPharmacokinetics

0

5

10

15

20

1-8d 9-30d 1-12m 1-6y 18-49y 50-74y 75-92y

Age

CL (ml/min/m

2 )

0

0,5

1

1,5

2

CL (ml/min; ml/min/kg)

CL (ml/min)CL (ml/min/m2)Cl (ml/min/kg)

From: Hayton WL, Stoeckel K. Clin Pharmacokin 1986;11:76-86From: Hayton WL, Stoeckel K. Clin Pharmacokin 1986;11:76-86

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Age-associated Changes in Ceftriaxone Age-associated Changes in Ceftriaxone PharmacokineticsPharmacokinetics

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;11:76-86From: Hayton WL, Stoeckel K. Clin Pharmacokin 1986;11:76-86

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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

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Theophylline Clearance and Pubertal Theophylline Clearance and Pubertal DevelopmentDevelopment

Kolski GB ym. AJDC 1987; 141: 282-7

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Efficacy of medicinal products Efficacy of medicinal products in the paediatric populationin the paediatric population

• Effect of G&D on efficacy

• PG-inhibitors and PDA

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Patent ductus arteriosus (PDA)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

31

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Adverse effects specific to the Adverse effects specific to the paediatric populationpaediatric population

• Corticosteroids

• Tetracyclines

• Discoloration of teeth

• ASA

• Reye -syndrome

• Quinolones

• Disturbed cartilage growth

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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

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

35©K. Hoppu 4.4.2008 *CHMP Guideline On Clinical Trials In Small Populations (www.emea.eu.int)

Clinical trials to demonstrate Clinical trials to demonstrate efficacy/safety in children must beefficacy/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?*