Transcript H. Seyberth 26.05.07 WS I

H. W. Seyberth
Department of Pediatrics
Philipps University, Marburg/Germany
Workshop:
Designs of human pharmacology trials for
paediatric populations
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
Physiology, Diseases and
Developmental Pharmacology
Appreciation of at least
five phases
of development
Very Preterm Newborn: Phase of survival
born at < 27 weeks of gestation
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
Pathophysiology:
Respiratory distress
Pulmonary hypertension
Patent ductus arteriosus
Apnea
Intraventricular hemorrhage
Retinopathy of prematurity (ROP)
Bronchopulmonary dysplasia
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
Term Newborn: Phase of Adaptation
age: birth up to 1 month
Pathophysiology:
Sepsis
Hyperbilirubinemia
Seizures
Hypocalcemia
Hypoglycemia
Malformations
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)
Infants and Toddler:
Phase of proliferation and growth
age: 22 days to 24 months
Pathophysiology:
Otitis media
Bronchiolitis
Febrile seizures
Rickets
Children:
Phase of Differentiation and Training
age: 2 to 11 years
Physiology:
Slower growth rate
Increased independence
Increased school performance
Shift to logical operations
Children:
Phase of Differentiation and Training
age: 2 to 11 years
Pathophysiology:
Accidence
Dysfunctions of the immune system:
Asthma/allergy
Juvenile rheumatoid arthritis
Autoimmune diseases
Neoplasm
Hyperkinesia
Enuresis
Organ transplantations
Epileptic syndromes
Obesity
Diabetes
Adolescents: Sexual Maturation
age: 12 to 17 years
Physiology:
Rapid body changes:
growth spurt
gonadal growth
Emotional instability
Adolescents: Sexual Maturation
age: 12 to 17 years
Pathophysiology:
Acne vulgaris
Endocrine dysfunctions
Accidence
Sexual transmitted diseases
Drug addiction
Doping
Pre-term Infant Term Newborn Infant/Toddler
Infant
28 days -23 months
< 36 weeks of
gestation
Survival
Child
Adolescent
2 - 11 years
12 - 17 years
0-27 days
Adaptation
Growth
Training
Maturation
Seyberth, in Pädiatrie, eds Speer/Gahr, 2005
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
An important dosage-principle in the NICU
• Given:
• Vd 
• Clearance 
• Result:
• Loading dose (LD) 
• Maintenance dose (MD) 
• Examples:
• Phenobarbital, Phenytoin,
Methylxanthine, Digoxin,
Aminoglykoside, Indometacin
Chloramphenicol, Furosemide
THEOPHYLLINE
Maintenance dose of drugs with renal elimination
DIGOXIN
(µg/kg/day)
20 -
(ml/h/kg)
100 -
15 -
75 -
10 -
50 -
5-
25 -
-
(mg/kg/day)
GENTAMYCINE
-
Preterm
Young
+ term children
neonates (< 8 y)
-
0
-
Adults
(> 50 y)
-
(mg/kg/day)
10 -
Adults
(< 50 y)
-
Preterm
Young
+ term children
neonates (< 8 y)
-
-
-
-
0
Total body clearence
Adults
(< 50 y)
Adults
(> 50 y)
Maintenance dose
30 20 -
510 -
-
Preterm
Young
+ term children
neonates (< 8 y)
-
-
0
-
Adults
(> 50 y)
-
-
Adults
(< 50 y)
-
Preterm
Young
+ term children
neonates (< 8 y)
-
-
-
0
Adults
(< 50 y)
Adults
(> 50 y)
PHARMACOKINETICS
PHARMACODYNAMICS
Resorption
Distribution
Receptor
Excretion
Signal transduction
Cellular reaction
Morphine plasma concentration [µg/l]
at time point of pain recovery
Medium analgesic dosage of morphine
in children with an age between 0 and 6 years
p < 0.01
40
30
dosis:
0.05 mg/kg/min infusion
rate until painlessness
20
10
0
0 - ½ year 2 - 4 year
n=5
n=5
6 year
n=4
(Olkkola et al., CPT 1988)
Indomethacin induces GFR reduction in young adults with
volume depletion and in preterm infants with sPDA
2 mg/kg/d
GFR
ml/min/1.73m2
100
with indo
- 12 %
91
80
without indo
80
60
40
0.2 mg/kg/d
20
19.5
11.7
adults
infants
- 40%
Congenital salt losing tubulopathies (SLTs)
Different age at manifestation and ontogeny of targets
(Jeck et al., AJ P 2005)
Furosemid-SLT : NKCC2
Polyhydramnios
12/12
Thiazid-SLT : NCCT
0/13
<1 year: 1/13
1-5 years: 4/13
Age at first
presentation
antenatal: 12/12
Postnatal
leading
symptoms
polyuria
hypokalemia
hyponatremia
hypotension (shock)
hypercalciuria
nephrocalcinosis
carpopedal spasms
hypomagnesemia
hypocalciuria
growth retardation
Affected
nephron
segment
thick ascending limb
6-13 years: 8/13
distal convolute
Adverse effects of geriatric heart failure therapy
applied to preterm infants with sPDA:
fluid restriction
marked volume depletion
renal hypoperfusion
furosemide
PG-stimulation
nephrocalcinosis
digoxin
arrhythmias with
cerebral bleeding
NSAID´s
ACE- inhibitor
intestinal perforation
renal failure
Pre-renal failure in the preterm infant with sPDA
filtration
v. afferens
prostaglandins
vasodilation
v. efferens
angiotensin II
vasoconstriction
Examples on long-term adverse effects of
medicines in early infancy and childhood
Target/ Organ
Drug
Effect
teeth
tetracyclines
discoloration/ enamel dysplasia
genital tract
cyclophosphamide
infertility/ovarian failure
immune system
tacrolimus
lymphoproliferation
diabetes
heart
antracyclines
alkylating agens
methylphenidate
cardiotoxicity
heart failure
cardiovascular events like myocard. infarct
CNS
phenobarbital
glucocorticoides
methylphenidate
cisplatin
attention and memory dysfunction
cerebral palsy
stroke
hearing loss
kidney
furosemide
nephrocalcinosis
bone
glucocorticoids
growth failure
There are marked differences in pediatric patiants
with respect to:
- Pharmacokinetics
- Pharmacodynamics
- Drug toxicity
- Longterm safety