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From neonates to adolescents

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

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From neonates to adolescents

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  1. 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

  2. Historical background • Sulfanilamide 1937 • Sulfisoxazole 1954 • Chloramphenicol 1958 • Thalidomide 1961 • Diethylstilbestrol (DES) 1971

  3. 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.

  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.

  5. Children = small adults =

  6. Growth & Development Growth and development – a continuum

  7. Major Developmental Periods • Prenatal development / prematurity • Birth - Rapid postnatal development • Prepuberty • Puberty • Postpubertal adolescence

  8. Variations in the pattern of pubertal changes in girls Marshall WA, Tanner JM. Arch Dis Child 1969;44(235):291-303.

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

  10. Effects of growth and development on: • Dosing • Size • Pharmacokinetics – ADME • Need for special formulations • Adverse effects • Efficacy

  11. 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

  12. Pharmacokinetics - Absorption • Bioavailability • Special formulations • Developmental differences? • Effects of food • Systemic absorption of topical preparations

  13. 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.

  14. Pharmacokinetics - GI Absorption • Physiology • Higher intragastric pH in newborns • Gastric emptying and intestinal mobility matures during first weeks of life

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

  16. 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...

  17. Pharmacokinetics - Distribution • Body compartments and G&D • Protein binding • Bilirubin displacement • Permeability of BBB

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

  19. Pharmacokinetics - Elimination • Metabolism • Postnatal development • Toddler peak • Pubertal slowing • Qualitative differences • Renal elimination

  20. Effects of Fetal Drug Metabolism No metabolism With metabolism

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

  22. Pharmacokinetics - Renal Elimination • Adaptation after birth • High renal elimination capacity in young children • Return to adult capacity level with pubertal development

  23. 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.

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

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

  26. 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

  27. Theophylline Clearance and Pubertal Development Kolski GB ym. AJDC 1987; 141: 282-7

  28. Efficacy of medicinal products in the paediatric population • Effect of G&D on efficacy • PG-inhibitors and PDA

  29. Adverse effects specific to the paediatric population • Corticosteroids • Tetracyclines • Discoloration of teeth • ASA • Reye -syndrome • Quinolones • Disturbed cartilage growth

  30. 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

  31. 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

  32. 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?* *CHMP Guideline On Clinical Trials In Small Populations (www.emea.eu.int)

  33. Is it ethical to perform paediatric drug research? Is it ethical not to perform paediatric drug research?

  34. 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

  35. 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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