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

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Presentation on theme: "From neonates to adolescents Kalle Hoppu, M.D., Ph.D. Director, Poison Information Centre, Helsinki University Central Hospital Docent (Ass. professor)"— Presentation transcript:

1 From neonates to adolescents Kalle Hoppu, M.D., Ph.D. 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 Member, WHO Expert Advisory Panel on Drug Evaluation Director FINPEDMED - Finnish Investigators Network for Pediatric Medicines

2 1 ©K. Hoppu 4.4.2008 Historical background Sulfanilamide 1937 Sulfisoxazole 1954 Chloramphenicol 1958 Thalidomide 1961 Diethylstilbestrol (DES)1971

3 2 ©K. Hoppu 4.4.2008

4 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 3

5 Burns L, Hodgman J, Cass A. fatal circulatory collapse in premature infants receiving chloramphenicol. New England Journal of Medicine 1959;261(26):1318-21. ©K. Hoppu 4.4.2008 4

6 5 Children = small adults = =

7 ©K. Hoppu 4.4.2008 6

8 7

9 8 Major Developmental Periods Prenatal development / prematurity Birth - Rapid postnatal development Prepuberty Puberty Postpubertal adolescence Growth and development – a continuum

10 9 ©K. Hoppu 4.4.2008 Variations in the pattern of pubertal changes in girls Marshall WA, Tanner JM. Arch Dis Child 1969;44(235):291-303.

11 10 ©K. Hoppu 4.4.2008 Marshall WA, Tanner JM. Arch Dis Child 1970;45(239):13-23 Variations in the pattern of pubertal changes in boys

12 11 ©K. Hoppu 4.4.2008 Effects of growth and development on: Dosing Size Pharmacokinetics – ADME Need for special formulations Adverse effects Efficacy

13 12 ©K. Hoppu 4.4.2008 Smaller size Smaller absolute dose Dose relative to size mg/kg mg/m 2 mg/kg 3/4 (allometric) Large body surface area to mass ratio Size related issues in dosing

14 13 ©K. Hoppu 4.4.2008 Pharmacokinetics - Absorption Bioavailability Special formulations Developmental differences? Effects of food Systemic absorption of topical preparations

15 14 ©K. Hoppu 4.4.2008 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.

16 15 ©K. Hoppu 4.4.2008 Pharmacokinetics - GI Absorption Physiology Higher intragastric pH in newborns Gastric emptying and intestinal mobility matures during first weeks of life

17 ©K. Hoppu 4.4.200816 From: Kearns GL et al. N Engl J Med 2003;349(12):1157-67.

18 17 ©K. Hoppu 4.4.2008 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

19 18 ©K. Hoppu 4.4.2008 Pharmacokinetics - Distribution Body compartments and G&D Protein binding Bilirubin displacement Permeability of BBB

20 ©K. Hoppu 4.4.200819 From: Kearns GL et al. N Engl J Med 2003;349(12):1157-67.

21 20 ©K. Hoppu 4.4.2008 Pharmacokinetics - Elimination Metabolism Postnatal development Toddler peak Pubertal slowing Qualitative differences Renal elimination

22 21 ©K. Hoppu 4.4.2008 With metabolism No metabolism Effects of Fetal Drug Metabolism

23 22 ©K. Hoppu 4.4.2008 From: Kearns GL et al. N Engl J Med 2003;349(12):1157-67.

24 23 ©K. Hoppu 4.4.2008 Pharmacokinetics - Renal Elimination Adaptation after birth High renal elimination capacity in young children Return to adult capacity level with pubertal development

25 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 24

26 25 ©K. Hoppu 4.4.2008 Age-associated Changes in Ceftriaxone Pharmacokinetics From: Hayton WL, Stoeckel K. Clin Pharmacokin 1986;11:76-86

27 26 ©K. Hoppu 4.4.2008 Age-associated Changes in Ceftriaxone Pharmacokinetics From: Hayton WL, Stoeckel K. Clin Pharmacokin 1986;11:76-86

28 27 ©K. Hoppu 4.4.2008 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

29 28 ©K. Hoppu 4.4.2008 Theophylline Clearance and Pubertal Development Kolski GB ym. AJDC 1987; 141: 282-7

30 29 ©K. Hoppu 4.4.2008 Efficacy of medicinal products in the paediatric population Effect of G&D on efficacy PG-inhibitors and PDA

31 ©K. Hoppu 4.4.2008 Patent ductus arteriosus (PDA) Allows 90% of RV output to bypass high-resistance pulmonary vascular bed in utero Postnatally, starts to close within rst few hours after birth In term infant closure usually complete by 72 h 30

32 31 ©K. Hoppu 4.4.2008 Adverse effects specific to the paediatric population Corticosteroids Tetracyclines Discoloration of teeth ASA Reye -syndrome Quinolones Disturbed cartilage growth

33 32 ©K. Hoppu 4.4.2008 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

34 33 ©K. Hoppu 4.4.2008 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

35 34 ©K. Hoppu 4.4.2008 *CHMP Guideline On Clinical Trials In Small Populations (www.emea.eu.int) 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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