1. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 0 |0 | 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. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 1 |1 | Historical background Sulfanilamide 1937 Sulfisoxazole 1954 Chloramphenicol 1958 Thalidomide 1961 Diethylstilbestrol (DES)1971

3. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 2 |2 |

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.

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.

6. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 5 |5 | Children = small adults = =

7. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 6 |6 | Growth & Development Growth and development – a continuum

9. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 8 |8 |

10. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 9 |9 |

11. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 10 | Major Developmental Periods Prenatal development / prematurity Birth - Rapid postnatal development Prepuberty Puberty Postpubertal adolescence

12. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 11 | Variations in the pattern of pubertal changes in girls Marshall WA, Tanner JM. Arch Dis Child 1969;44(235):291-303.

13. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 12 | Variations in the pattern of pubertal changes in boys Marshall WA, Tanner JM. Arch Dis Child 1970;45(239):13-23

14. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 13 | Effects of growth and development on: Dosing – Size – Pharmacokinetics – ADME – Need for special formulations Adverse effects Efficacy

15. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 14 | 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

16. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 15 | Pharmacokinetics - Absorption Bioavailability – Special formulations – Developmental differences? Effects of food Systemic absorption of topical preparations

17. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 16 | 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.

18. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 17 | Pharmacokinetics - GI Absorption Physiology –Higher intragastric pH in newborns –Gastric emptying and intestinal mobility matures during first weeks of life

19. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 18 | From: Kearns GL et al. N Engl J Med 2003;349(12):1157-67.

20. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 19 | 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...

21. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 20 | Pharmacokinetics - Distribution Body compartments and G&D Protein binding Bilirubin displacement Permeability of BBB

22. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 21 | From: Kearns GL et al. N Engl J Med 2003;349(12):1157-67.

23. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 22 | Pharmacokinetics - Elimination Metabolism – Postnatal development – Toddler peak – Pubertal slowing – Qualitative differences Renal elimination

24. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 23 | With metabolism No metabolism Effects of Fetal Drug Metabolism

25. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 24 | From: Kearns GL et al. N Engl J Med 2003;349(12):1157-67.

26. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 25 | Pharmacokinetics - Renal Elimination Adaptation after birth High renal elimination capacity in young children Return to adult capacity level with pubertal development

27. 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.

28. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 27 | Age-associated Changes in Ceftriaxone Pharmacokinetics From: Hayton WL, Stoeckel K. Clin Pharmacokin 1986;11:76-86

29. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 28 | Age-associated Changes in Ceftriaxone Pharmacokinetics From: Hayton WL, Stoeckel K. Clin Pharmacokin 1986;11:76-86

30. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 29 | 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

31. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 30 | Theophylline Clearance and Pubertal Development Kolski GB ym. AJDC 1987; 141: 282-7

32. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 31 | Efficacy of medicinal products in the paediatric population Effect of G&D on efficacy – PG-inhibitors and PDA

33. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 32 | Adverse effects specific to the paediatric population Corticosteroids Tetracyclines – Discoloration of teeth ASA – Reye -syndrome Quinolones – Disturbed cartilage growth

34. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 33 | 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

35. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 34 | 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. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 35 | *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?*

37. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 36 | Is it ethical to perform paediatric drug research? Is it ethical not to perform paediatric drug research?

38. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 37 | 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

39. Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 2007 38 | 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