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2nd Joint Annual Meeting – Club Phase I and AGAH Positioning Human Pharmacology for the Future Bad Homburg v.d.H., April 26 and 27, 2007 H. W. Seyberth.

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Presentation on theme: "2nd Joint Annual Meeting – Club Phase I and AGAH Positioning Human Pharmacology for the Future Bad Homburg v.d.H., April 26 and 27, 2007 H. W. Seyberth."— Presentation transcript:

1 2nd Joint Annual Meeting – Club Phase I and AGAH Positioning Human Pharmacology for the Future Bad Homburg v.d.H., April 26 and 27, 2007 H. W. Seyberth Department of Pediatrics Philipps University, Marburg/Germany Workshop: Designs of human pharmacology trials for paediatric populations paediatric populations

2 Physiology, Diseases and Developmental Pharmacology

3 Appreciation of at least five phases of development

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5 Physiology: Large body surface Increased skin permeability Reduced surfactant synthesis Aortopulmonary shunts Immaturity of the brain stem No ciruclatory autoregulation Incomplete retinal vascularisation Very Preterm Newborn: Phase of survival born at < 27 weeks of gestation

6 Pathophysiology: Respiratory distress Pulmonary hypertension Patent ductus arteriosus Apnea Intraventricular hemorrhage Retinopathy of prematurity (ROP) Bronchopulmonary dysplasia Very Preterm Newborn: Phase of survival born at < 27 weeks of gestation

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8 Term Newborn: Phase of Adaptation age: birth up to 1 month Physiology: Large body surface Increased skin permeability Increased body water Decreased blood brain barrier Incomplete neuronal maturation Increased hemolysis

9 Pathophysiology: Sepsis Hyperbilirubinemia Seizures Hypocalcemia Hypoglycemia Malformations Term Newborn: Phase of Adaptation age: birth up to 1 month

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11 Infants and Toddler: Phase of proliferation and growth age: 22 days to 24 months Physiology: Small airways Ongoing cerebral myelination Naive (incompetent) immune system Large liver and kidney (increased clearances)

12 Pathophysiology: Otitis media Bronchiolitis Febrile seizures Rickets Infants and Toddler: Phase of proliferation and growth age: 22 days to 24 months

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15 Children: Phase of Differentiation and Training age: 2 to 11 years Physiology: Slower growth rate Increased independence Increased school performance Shift to logical operations

16 Pathophysiology: Accidence Dysfunctions of the immune system: Asthma/allergy Juvenile rheumatoid arthritis Autoimmune diseases Neoplasm Hyperkinesia Enuresis Organ transplantations Epileptic syndromes Obesity Diabetes Children: Phase of Differentiation and Training age: 2 to 11 years

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18 Adolescents: Sexual Maturation age: 12 to 17 years Physiology: Rapid body changes: growth spurt gonadal growth Emotional instability

19 Adolescents: Sexual Maturation age: 12 to 17 years Pathophysiology: Acne vulgaris Endocrine dysfunctions Accidence Sexual transmitted diseases Drug addiction Doping

20 Pre-term Infant < 36 weeks of gestation Term Newborn Infant 0-27 days Infant/Toddler 28 days -23 months Child years Adolescent years Survival Survival Adaptation Adaptation Growth Training Maturation Maturation Seyberth, in Pädiatrie, eds Speer/Gahr, 2005

21 Pharmacokinetic differences in the term and preterm infants Absorption:  Gastric HCI-production  Bile flow  Bacterial intestinal growth  Enterohepatic circulation Distribution:  Body water  Body fat  Muscular mass  Plasma protein binding Liver metabolism:  Hydroxylation  Glucoronidation Renale excretion:  GFR  Tubular function

22 An important dosage-principle in the NICU Given: Result: Examples: V d  Clearance  Loading dose (LD)  Maintenance dose (MD)  Phenobarbital, Phenytoin, Methylxanthine, Digoxin, Aminoglykoside, Indometacin Chloramphenicol, Furosemide

23 (µg/kg/day) (mg/kg/day) (ml/h/kg) Total body clearence Maintenance dose DIGOXIN GENTAMYCINE Preterm + term neonates Young children (< 8 y) Adults (< 50 y) Adults (> 50 y) Preterm + term neonates Young children (< 8 y) Adults (< 50 y) Adults (> 50 y) Preterm + term neonates Young children (< 8 y) Adults (< 50 y) Adults (> 50 y) Preterm + term neonates Young children (< 8 y) Adults (< 50 y) Adults (> 50 y) THEOPHYLLINE Maintenance dose of drugs with renal elimination

24 Resorption Distribution Excretion Receptor Signal transduction Cellular reaction PHARMACODYNAMICS PHARMACODYNAMICS PHARMACOKINETICS PHARMACOKINETICS

25 Medium analgesic dosage of morphine in children with an age between 0 and 6 years (Olkkola et al., CPT 1988) ½ year n = 5 6 year n = year n = 5 Morphine plasma concentration [µg/l] at time point of pain recovery p < 0.01 dosis: 0.05 mg/kg/min infusion rate until painlessness

26 Indomethacin induces GFR reduction in young adults with volume depletion and in preterm infants with sPDA GFR ml/min/1.73m 2 2 mg/kg/d 0.2 mg/kg/d % - 40% adultsinfants without indo with indo

27 Congenital salt losing tubulopathies (SLTs) Different age at manifestation and ontogeny of targets (Jeck et al., AJ P 2005) (Jeck et al., AJ P 2005) Thiazid - SLT : NCCT Furosemid -SLT : NKCC2 Polyhydramnios 12/12 0/13 Postnatal leading symptoms polyuria hyponatremia hypotension (shock) hypercalciuria nephrocalcinosis hypokalemia carpopedal spasms hypomagnesemia hypocalciuria growth retardation Age at first presentation antenatal: 12/12 <1 year: 1/ years: 4/ years: 8/13 thick ascending limbdistal convolute Affected nephron segment

28 fluid restriction furosemide digoxin NSAID´s ACE- inhibitor Adverse effects of geriatric heart failure therapy applied to preterm infants with sPDA: arrhythmias with cerebral bleeding marked volume depletion renal hypoperfusion PG-stimulation nephrocalcinosis intestinal perforation renal failure

29 Pre-renal failure in the preterm infant with sPDA filtration v. afferens v. efferens vasodilationvasoconstriction prostaglandins angiotensin II

30 Examples on long-term adverse effects of medicines in early infancy and childhood Target/ OrganDrugEffect teethtetracyclinesdiscoloration/ enamel dysplasia genital tractcyclophosphamideinfertility/ovarian failure immune systemtacrolimuslymphoproliferation diabetes heartantracyclines alkylating agens methylphenidate cardiotoxicity heart failure cardiovascular events like myocard. infarct CNSphenobarbital glucocorticoides methylphenidate cisplatin attention and memory dysfunction cerebral palsy stroke hearing loss kidneyfurosemidenephrocalcinosis boneglucocorticoidsgrowth failure

31 There are marked differences in pediatric patiants with respect to: - Pharmacokinetics - Pharmacodynamics - Drug toxicity - Longterm safety


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