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Karel Allegaert, MD PhDUZ Leuven
determinants of variability in disposition of exogenous compounds in neonates
Clinical research supported by the Fund for Scientific Research, Flanders (Belgium) (FWO Vlaanderen) by a Fundamental Clinical Investigatorship (2009-2014)
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Neonatologists are working at the fast lane of (developmental) life, age or size/weight are the most significant covariates
in general, drug clearance is low. This – however – does not exclude extensive interinidividual variability within the neonatal population (size log value)
This extensive interindividual variability in drug disposition necessitates the search for covariates within the neonatal population
There is no such thing as ‘an isolated neonatal liver/kidney’main route of clearance should not be similar in neonates compared to adults
conclusions
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developmental (dis)continuum
fetus
newborn
infant
toddler
child
adolescent
adult
weight x 2 5 mx 3 1 y
caloric needs x 3-4 1 y
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compound Exposure
Response
AbsorptionDistribution
Receptor InteractionBiotransformation
Excretion
AbsorptionDistribution
Receptor InteractionBiotransformation
Excretion
environmental genetics
diseasegrowthmaturation
extensive interindividual variability
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drug
Dose Conc Effect
pharmacokinetics pharmacodynamics
developmental pharmacology
PK : what the body does to the drug: conc/timePD: what the drug does to the body : conc/effect
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AbsorptionAbsorption
Metabolism Metabolism
EliminationElimination
DistributionDistribution
exposureexposure
The combination of ADME will determine the time/conc profile
This time/conc profile together with aspects of the therapeutic target/receptor will determine the conc/effect profile
pattern recognition: covariates ?
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hepatic
renalBody composition
Formula dependent
Ref: Kearns et al, NEJM 2003
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Ref: Rakhmanina et al, 2006
body composition is age-dependent
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drug metabolism: relation to weight/age ?
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Ref: Nelson’s textbook Pediatrics
brain/body fraction
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Biol Neonate 1998;74:351-62
distribution volume: hydrophylic drugs
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0
10
20
30
40
50
60
70
80
10 100 1000
Post conception age (weeks)
Perip
hera
l Vol
ume
of
Dist
ribut
ion
(l/70
kg)
Allegaert 2003 Allegaert 2004Ganry 1992 Flandin 1988Cavellat 1984 Pons 1992Autret 1993
distribution volume: hydrophylic drugs
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distribution volume: lipophylic drugs
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hepatic
renalBody composition
Formula dependent
Ref: Kearns et al, NEJM 2003
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Ref: Weinshilboum, NEJM 2003
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biotransformation
DrugPhase IPhase I
CYPsEsterases
Dehydrogenases
CYPsEsterases
Dehydrogenases
Phase IIPhase II
UGTsNATsSTsMTsGSTs
UGTsNATsSTsMTsGSTs
MetaboliteMetabolite
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CYP3A7-CYP3A4 “Switch”
0.00
0.50
1.00
1.50
<30 wk >30 wk <24 hr 1-7 d 8-28 d 1-3 mo 3-12 mo >1 yr Adult
0.15
0.10
0.05
0.00
Fetus Newborn
DH
EA
16
-hyd
roxy
lati
on
CYP3A7
Tes
tost
eron
e 6
-hyd
roxy
lati
on
CYP3A4
drug metabolism: co-variates - age
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drug metabolism: co-variates - age
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drug metabolism: ontogeny and polymorphism ?
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drug metabolism: ontogeny and polymorphism
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glucuronidation: postnatal age-dependent
Bouwmeester et al, Br J Anaesth 2004
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CYP2B6/3A434 %
UGT77 %
propofol clearance is metabolic clearance
High capacity, low specificity : glucuronidationLow capacity, high specificity: CYP2B6
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propofol clearance in neonates compared to toddlers
Pediatr Anesth 2007
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Br J Anaesth 2007
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PMA was the most predictive covariate for clearance (p<0.001) when parameterized as [CLstd x (PMA/38)11.5]. Standardized propofol clearance (CLstd) at 38 weeks PMA was0.029 L/min
The addition of a fixed value in neonates with a postnatal age of≥ 10 days further improved the model (p < 0.001) and resultedin the equation [CLstd . (PMA/38)11.5 + 0.03 L/min] for neonates ≥10 days.
Br J Anaesth 2007
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Br J Anaesth 2007
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hepatic
renalBody composition
Formula dependent
Ref: Kearns et al, NEJM 2003
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0
10
20
30
40
50
60
0 5 10 15 20 250
20
40
60
80
100
120
0 20 40 60 80 100 120
15 full term15 full term
23 premature23 premature
Guignard et al, J Pediatr 1975 Koren et al, Clin Pharmacol Ther 1975
GFR/postnatal age GFR/gentamicin
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Biol Neonate 1998;74:351-62
renal drug elimination
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Guignard JP. Pediatr Research 1994
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renal drug elimination: impact of age at birth
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Guignard JP. Pediatr Research 1994
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renal drug elimination: predictability/postnatal age
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renal drug elimination: co-medication
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0
0,5
1
1,5
2
2,5
3
3,5
4
20 25 30 35 40
Postmenstrual age (weeks)
Cle
aran
ce (L
/h/7
0kg)
CL individual CL populationCL population ibuprofen CL ibuprofen
Br J Clin Pharmacol 2007 (glycopeptides)
renal drug elimination: age and NSAID’s
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renal drug elimination: disease characteristics
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Ref: Weinshilboum, NEJM 2003
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extensive interindividual variability
Pattern recognitionage sizeco-medicationdisease characteristicspolymorphisms
improved predictability
collaborative efforts, ‘sized’ techniquespopulation pklow volume samples
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Neonatologists are working at the fast lane of (developmental) life, age or size/weight are the most significant covariates
in general, drug clearance is low. This – however – does not exclude extensive interinidividual variability within the neonatal population (size log value)
This extensive interindividual variability in drug disposition necessitates the search for covariates within the neonatal population
There is no such thing as ‘an isolated neonatal liver/kidney’main route of clearance should not be similar in neonates compared to adults
conclusions