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Historical background

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Presentation on theme: "Historical background"— Presentation transcript:

0 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

1 Historical background
Sulfanilamide Sulfisoxazole Chloramphenicol Thalidomide Diethylstilbestrol (DES) 1971 ©K. Hoppu

2 ©K. Hoppu

3 Silverman W, Andersen D, Blanc W, Crozier D
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: ©K. Hoppu

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

5 Children = small adults
©K. Hoppu

6 ©K. Hoppu

7 ©K. Hoppu

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

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

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

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

12 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 ©K. Hoppu

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

14 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): ©K. Hoppu

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

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

17 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 ©K. Hoppu

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

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

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

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

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

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

24 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): ©K. Hoppu

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

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

27 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 ©K. Hoppu

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

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

30 Patent ductus arteriosus (PDA)
EUDIPHARM 6th European Course Evaluation of Medicinal Products in Children 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 ©K. Hoppu ©K. Hoppu

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

32 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 ©K. Hoppu

33 Effect of G&D on efficacy to be suspected Antidepressants
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 ©K. Hoppu

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


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