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.

2nd Joint Annual Meeting – Club Phase I and AGAHPositioning 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: Workshop:

Designs of human pharmacology trials forDesigns of human pharmacology trials for

paediatric populationspaediatric populations

Physiology, Diseases and

Developmental Pharmacology

Appreciation of at least

five phases

of development

Physiology:

Large body surface Increased skin permeability Reduced surfactant synthesis

Aortopulmonary shuntsImmaturity of the brain stem No ciruclatory autoregulation Incomplete retinal vascularisation

Very Preterm Newborn: Phase of survivalborn at < 27 weeks of gestation

Pathophysiology:

Respiratory distressPulmonary hypertensionPatent ductus arteriosusApneaIntraventricular hemorrhageRetinopathy of prematurity (ROP)Bronchopulmonary dysplasia

Very Preterm Newborn: Phase of survivalborn at < 27 weeks of gestation

Term Newborn: Phase of Adaptationage: birth up to 1 month

Physiology:

Large body surfaceIncreased skin permeabilityIncreased body water Decreased blood brain barrierIncomplete neuronal maturationIncreased hemolysis

Pathophysiology:

SepsisHyperbilirubinemiaSeizures HypocalcemiaHypoglycemiaMalformations

Term Newborn: Phase of Adaptationage: birth up to 1 month

Infants and Toddler: Phase of proliferation and growthage: 22 days to 24 months

Physiology:

Small airways Ongoing cerebral myelination Naive (incompetent) immune system

Large liver and kidney (increased clearances)

Pathophysiology:

Otitis mediaBronchiolitisFebrile seizuresRickets

Infants and Toddler:

Phase of proliferation and growth

age: 22 days to 24 months

Children:Phase of Differentiation and Trainingage: 2 to 11 years

Physiology:

Slower growth rateIncreased independenceIncreased school performanceShift to logical operations

Pathophysiology:

AccidenceDysfunctions of the immune system:

Asthma/allergyJuvenile rheumatoid arthritisAutoimmune diseasesNeoplasm

HyperkinesiaEnuresisOrgan transplantationsEpileptic syndromesObesityDiabetes

Children: Phase of Differentiation and Trainingage: 2 to 11 years

Adolescents: Sexual Maturation

age: 12 to 17 years

Physiology:

Rapid body changes:growth spurtgonadal growth

Emotional instability

Adolescents: Sexual Maturationage: 12 to 17 years

Pathophysiology:

Acne vulgarisEndocrine dysfunctionsAccidenceSexual transmitted diseasesDrug addictionDoping

Pre-term InfantPre-term Infant

< 36 weeks of < 36 weeks of gestationgestation

Term Newborn Term Newborn InfantInfant

0-27 days0-27 days

Infant/ToddlerInfant/Toddler

28 days -23 months28 days -23 months

ChildChild

2 - 11 years2 - 11 years

AdolescentAdolescent

12 - 17 years12 - 17 years

SurvivalSurvival AdaptationAdaptation GrowthGrowth TrainingTraining MaturationMaturation

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:

• Result:

• Examples:

• Vd

• Clearance

• Loading dose (LD) • Maintenance dose (MD)

• Phenobarbital, Phenytoin, Methylxanthine, Digoxin, Aminoglykoside, Indometacin Chloramphenicol, Furosemide

-

-

-

-

- - - - -

- - - - - - - - - -

- - - - -

- -

-

-

-

-

-

-

-(µg/kg/day)

(mg/kg/day)(mg/kg/day)

(ml/h/kg)Total body clearenceTotal body clearence

Maintenance doseMaintenance dose

DIGOXINDIGOXIN

GENTAMYCINEGENTAMYCINE

Preterm+ term

neonates

Youngchildren(< 8 y)

Adults(< 50 y)

Adults(> 50 y)

Preterm+ term

neonates

Youngchildren(< 8 y)

Adults(< 50 y)

Adults(> 50 y)

Preterm+ term

neonates

Youngchildren(< 8 y)

Adults(< 50 y)

Adults(> 50 y)

Preterm+ term

neonates

Youngchildren(< 8 y)

Adults(< 50 y)

Adults(> 50 y)

THEOPHYLLINETHEOPHYLLINEMaintenance dose of drugs with renal eliminationMaintenance dose of drugs with renal elimination

20

15

10

5

0

10

5

0

100

75

50

25

0

30

20

10

0

Resorption

Distribution

Excretion

Receptor

Signal transduction

Cellular reaction

PHARMACODYNAMICSPHARMACODYNAMICS PHARMACODYNAMICSPHARMACODYNAMICS PHARMACOKINETICSPHARMACOKINETICS PHARMACOKINETICSPHARMACOKINETICS

Medium analgesic dosage of morphine

in children with an age between 0 and 6 years

(Olkkola et al., CPT 1988)

0

10

20

30

40

0 - ½ year n = 5

6 year n = 4

2 - 4 year n = 5M

orp

hin

e p

lasm

a c

on

cen

trat

ion

[µg

/l]a

t tim

e p

oin

t of p

ain

re

cove

ry

p < 0.01

dosis:0.05 mg/kg/min infusionrate until painlessness

Indomethacin induces GFR reduction in young adults with volume depletion and in preterm infants with sPDA

GF

Rm

l/min

/1.7

3m2

2 mg/kg/d

0.2 mg/kg/d

91

19.5

- 12 %

- 40%

adults infants

8080

60

40

20

100

11.7

without indo

with indo

Congenital salt losing tubulopathies (SLTs)Congenital salt losing tubulopathies (SLTs)Different aDifferent age at manifestation and ontogeny of targets ge at manifestation and ontogeny of targets (Jeck et al., AJ P 2005)(Jeck et al., AJ P 2005)

Thiazid-SLT : NCCTFurosemid-SLT : NKCC2

Polyhydramnios 12/12 0/13

Postnatal leading symptoms

polyuria hyponatremiahypotension (shock) hypercalciurianephrocalcinosis

hypokalemiacarpopedal spasms hypomagnesemiahypocalciuriagrowth retardation

Age at first

presentation antenatal: 12/12

<1 year: 1/13 1-5 years: 4/13

6-13 years: 8/13

thick ascending limb distal convoluteAffected nephron segment

fluid restriction

furosemide

digoxin

NSAID´s ACE- inhibitor

Adverse effects of geriatric heart failure therapy Adverse effects of geriatric heart failure therapy applied to preterm infants with sPDA:applied to preterm infants with sPDA:

arrhythmias with cerebral bleeding

marked volume depletion renal hypoperfusion

PG-stimulationnephrocalcinosis

intestinal perforationrenal failure

Pre-renal failure in the preterm infant with sPDAPre-renal failure in the preterm infant with sPDA

filtration

v. afferens v. efferens

vasodilation vasoconstrictionprostaglandins angiotensin II

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 dysfunctioncerebral palsy strokehearing loss

kidney furosemide nephrocalcinosis

bone glucocorticoids growth failure

There are marked differences in pediatric patiants with respect to:

- Pharmacokinetics

- Pharmacodynamics

- Drug toxicity

- Longterm safety