Transcript Special challenges in paediatric recruitment

determinants of variability in disposition of
exogenous compounds in neonates
Karel Allegaert, MD PhD
UZ Leuven
Clinical research supported by the Fund for Scientific Research, Flanders (Belgium)
(FWO Vlaanderen) by a Fundamental Clinical Investigatorship (2009-2014)
conclusions
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
developmental (dis)continuum
fetus
newborn
weight
caloric needs
infant
toddler
child
adolescent
adult
x2
x3
x 3-4
5m
1y
1y
extensive interindividual variability
disease
growth
maturation
environmental
compound
genetics
Absorption
Distribution
Receptor Interaction
Biotransformation
Excretion
Exposure
Response
developmental pharmacology
drug
Dose
pharmacokinetics
Conc
Effect
pharmacodynamics
PK : what the body does to the drug: conc/time
PD: what the drug does to the body : conc/effect
pattern recognition: covariates ?
Absorption
Distribution
The combination of ADME will
determine the time/conc profile
exposure
This time/conc profile together with
aspects of the therapeutic
target/receptor will determine the
conc/effect profile
Elimination
Metabolism
hepatic
Body composition
renal
Formula dependent
Ref: Kearns et al, NEJM 2003
body composition is age-dependent
Ref: Rakhmanina et al, 2006
drug metabolism: relation to weight/age ?
brain/body fraction
Ref: Nelson’s textbook Pediatrics
distribution volume: hydrophylic drugs
Biol Neonate 1998;74:351-62
distribution volume: hydrophylic drugs
Peripheral Volume of
Distribution (l/70kg)
80
Allegaert 2003
Ganry 1992
Cavellat 1984
Autret 1993
70
60
Allegaert 2004
Flandin 1988
Pons 1992
50
40
30
20
10
0
10
100
Post conception age (weeks)
1000
distribution volume: lipophylic drugs
hepatic
Body composition
renal
Formula dependent
Ref: Kearns et al, NEJM 2003
Ref: Weinshilboum, NEJM 2003
biotransformation
Phase I
Drug
Phase II
Metabolite
CYPs
Esterases
Dehydrogenases
UGTs
NATs
STs
MTs
GSTs
Metabolite
drug metabolism: co-variates - age
CYP3A7-CYP3A4 “Switch”
1.50
CYP3A4
DHEA 16a-hydroxylation
CYP3A7
1.00
0.10
0.50
0.05
0.00
0.00
<30 wk >30 wk
Fetus
<24 hr
1-7 d
8-28 d
1-3 mo 3-12 mo
Newborn
>1 yr
Adult
Testosterone 6b-hydroxylation
0.15
drug metabolism: co-variates - age
drug metabolism: ontogeny and polymorphism ?
drug metabolism: ontogeny and polymorphism
glucuronidation: postnatal age-dependent
Bouwmeester et al, Br J Anaesth 2004
propofol clearance is metabolic clearance
High capacity, low specificity : glucuronidation
Low capacity, high specificity: CYP2B6
CYP2B6/3A4
34 %
UGT
77 %
propofol clearance in neonates compared to toddlers
Pediatr Anesth 2007
Br J Anaesth 2007
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 was
0.029 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 resulted
in the equation [CLstd . (PMA/38)11.5 + 0.03 L/min] for neonates ≥
10 days.
Br J Anaesth 2007
Br J Anaesth 2007
hepatic
Body composition
renal
Formula dependent
Ref: Kearns et al, NEJM 2003
GFR/postnatal age
GFR/gentamicin
60
120
50
15 full term
23 premature
100
40
80
30
60
20
40
10
20
0
0
0
5
10
15
Guignard et al, J Pediatr 1975
20
25
0
20
40
60
80
100
Koren et al, Clin Pharmacol Ther 1975
120
renal drug elimination
Biol Neonate 1998;74:351-62
Guignard JP. Pediatr Research 1994
renal drug elimination: impact of age at birth
Guignard JP. Pediatr Research 1994
renal drug elimination: predictability/postnatal age
renal drug elimination: co-medication
renal drug elimination: age and NSAID’s
CL individual
CL population ibuprofen
Clearance (L/h/70kg)
4
CL population
CL ibuprofen
3,5
3
2,5
2
1,5
1
0,5
0
20
25
30
35
Postmenstrual age (weeks)
Br J Clin Pharmacol 2007 (glycopeptides)
40
renal drug elimination: disease characteristics
Ref: Weinshilboum, NEJM 2003
extensive interindividual variability
Pattern recognition
age
size
co-medication
disease characteristics
polymorphisms
improved predictability
collaborative efforts, ‘sized’ techniques
population pk
low volume samples
conclusions
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