From neonates to adolescents

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


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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.

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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Growth & DevelopmentGrowth & Development

Growth and development – a continuumGrowth and development – a continuum


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Major Developmental PeriodsMajor 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

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

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:Effects of growth and development 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 AbsorptionPharmacokinetics - 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

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 - DistributionPharmacokinetics - Distribution

Body compartments and G&D

Protein binding

Bilirubin displacement

Permeability of BBB


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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


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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.


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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


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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


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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 Development

Theophylline Clearance and Pubertal Development

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


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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


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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


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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 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


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?*


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Is it ethical to perform paediatri

c drug research

?

Is it ethical not to

perform paediatric

drug research?


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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


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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

From neonates to adolescents

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