Page 1
developmental clinical pon the use of drugs in
K Allegaert
Neonatal IntensivDivision of WomaUniversity Hospita
clinical research supported by the Clinical
pharmacologyn children
ve Care Unitan and Childals Leuven, Belgium
l Research Fund of the University Hospitals
Page 2
Children are not sm
limited dataoff la
specific needsdipedi
specdiffediffdiffe
impact of developmenta
bodyheparenarena
ontollallom
inter
mall adults
abel/unlicensed
t i i latric vialscific diseaseserent pathophysiology
t t ti l terent maturational anatomy
al pharmacokinetics
y compositionaticalal
ogenytmetry
rindividual variability
Page 3
Recent European Medicines
141 licensed dru47 pediatric ind47 pediatric ind
HIV
Un-licensed/ off-label use
60-80 % NIC40-60 % hos20 40 % first20-40 % first
Adverse drug reaction
s Evaluation Agency g y
gsicationication
V, vaccination
CU-PICUspital settingt line/family physiciant line/family physician
Page 4
relevance of a
99-02
Number of neonates 129
Neonatal survival (day 28) 96 %Gestational age (weeks) 28 (24-30)Gestat o a age ( ee s) 8 ( 30)Birth weight (gram) 1047 (346)Prenatal indomethacin 8 %Prenatal betamethasone 78 %ibuprofen co-administration n.a.ibuprofen co administration n.a. Peak amikacin (mg/l) 45.7 (17.8)Trough amikacin (mg/l) 8.2 (4.4)
Peak in target zone 94 %Peak in target zone 94 %Trough in target zone 31 %Both in target zone 22 %
a paediatric vial
02-9/04 9/04-9/05
75 56
93 % 98 %28 (24-30) 28 (24-30)8 ( 30) 8 ( 30)1130 (332) 1080 (314)3 % 4 %76 % 82 %52 % 23 %52 % 23 %38.3 (13.1) 40.9 (9.1)4.8 (2.6) 4.3 (1.8)
95 % 98 %95 % 98 %63 % 73 %58 % 72 %
Page 5
drug interactions
Br J Clin Pha
s
armacol 2006
Page 6
developmental neuspinal cordspinal cord
Ruda et al. Science 2000; 189: 628-31/
uro-anatomy
Maximal effect inMaximal effect in rats: 6-9 days (Anand & Scalzo 2000)
No effect in rats: 14 days(Ruda et al. 2000)
Rat - Human
0 day - 24 wks GA
7 days - full-term
14 days - 1-year-old
/ Walker et al. Pain 2003; 105: 185-95
Page 7
neuro-anatomical
Ruda et al. Science 2000/
l changes: spinal cord
0/ Walker et al. Pain 2003
Page 8
developmental nnephrology
Page 9
from paediatricc life to adulthood
Page 10
from adulthood bback to paediatrics
Page 11
developmental p
dru
Dose Con
pharmacokinetics
harmacokinetics
ug
nc Effect
pharmacodynamics
Page 13
hepatic
Body composition
Ref: Kearns et
renal
Formulation/bio-availability
t al, NEJM 2003
Page 14
Methohexital (B
3
2,5
3
1 5
2
1
1,5
0
0,5
0< 6 m 6 tot 12 1 t
Mean mg/kg of drug to enab
based on Westrin et al, 199
Brietal)
to 3 y 4 to 7 y 8 to 16 y
ble endotracheal intubation
92 and Naulaers et al, 1997
Page 15
brain/body fracti
Ref: Nelson’s textbook
ion
k Pediatrics
Page 16
B d iti fBody composition f
Route mediated bRoute mediated brp
Hepatic function
CYP tglucuronidation pg p
Renal function nRenal function na
f t/ t l blfat/water soluble
bio-availabilitybio availabilityroutepH
tramadolparacetamol/morphinep p
non selective COX inhibitorsnon selective COX inhibitorsamikacin clearance
Page 17
hepatic
Body compositionAge-dependent
Ref: Kearns et
renal
Formula dependent
al, NEJM 2003
Page 18
Ref: Rakhmanina et al, 2006
Page 19
distribution volum
7000
8000
5000
6000
7000
3000
4000
0
1000
2000
1 10
time-concentrations of propiv bolus administration of 3
me: lipophylic drugs
propofol (ng/ml)/log min
100 1000 10000
ofol observed following mg/kg in 25 neonates
Page 20
distribution volum
Present
Number of patients 9
Age (range) 4-25 days
Weight (kg, range) 0.9-3.8
Propofol dose (mg/kg, bolus) 3
Pharmacokinetic model 2-stage, ope
3 compartm
Vc (l/kg) 0 41Vc (l/kg) 0.41
Vss (l/kg) 4
Clearance (ml/kg/min) 24.01
me: lipophylic drugs
Murat Saint-Maurice
12 10
1-3 years 4-7 years
8.7-18.9 17-24
3 2.5
en 2-stage, open 2-stage, open
ent 3 compartment 3 compartment
0 95 0 720.95 0.72
8.17 10.9
43 31
Page 21
distribution volum
70
80
of
g)
50
60ol
ume
on
(l/70
kg
30
40
hera
l Vrib
utio
n
10
20
Perip Dist
010
Post conPost con
Paediatr Anaesth
me: hydrophylic drugs
Allegaert 2003 Allegaert 2004Ganry 1992 Flandin 1988Cavellat 1984 Pons 1992A t t 1993Autret 1993
100 1000
nception age ( eeks)nception age (weeks)
h 2005;15:282-92
Page 22
distribution volum
Biol Neonate 19
me: hydrophylic drugs
998;74:351-62
Page 23
hepatic
Body compositionAge-dependent
Ref: Kearns e
renal
route dependent/bio-availability
et al, NEJM 2003
Page 24
gastro-intestinaal track/bio-availability
Page 25
gastro-intestinaal track/bio-availability
Page 26
gastro-intestinaal track/bio-availability
Rectal route
Oral route
Page 27
gastro-intestina
dose-concentrarectal paracetam
•Solid box= 5•Values outsicentile are shindividually
al track/bio-availability
ation variability / /mol 12.5 mg/kg/6h
50th centilede the 97.5%
hown
Page 28
gastro-intestina
1 61.8
ity
11.21.41.6
vaila
bil
0 40.60.8
1
ve B
ioa
00.20.4
10
Rela
ti
10
Log Post-ges
al track/bio-availability
capsule suppositorytriglyceride suppository triglyceride suppository
100 1000100 1000
station age (weeks)
Page 29
hepatic
Body compositionAge-dependent
Ref: Kearns e
renal
route dependent/bio-availability
et al, NEJM 2003
Page 30
Ref: Weinshilbouum, NEJM 2003
Page 31
drug metabolism
Polymor(e.g. CY
Iso-enzymphenotypiAge
e.g. postnatal agepostmenstrual age
Environe.g. m
co
current clinical ph
m: co-variates
rphismsYP2D6)
me specificc activity co-morbidity
e.g. type of surgery
mentalmaternal smokingo-medication
armacology, 2007
Page 32
drug metabolism
hepatic mhepatic m
phase 1phase 1non-synthetic reactions
e.g. CYP2D6e.g. CYP2D6
m: co-variates
metabolismmetabolism
phase 2th ti tisynthetic reactions
e.g. paracetamol, himorphine
Page 33
drug metabolism
CYP3A7-CYP
1.50
CYP3A7
ion
CYP3A7
1.00
roxy
lati
0.506α-h
ydr
0.50
HEA
16
0.00<30 wk >30 wk <24 hr 1-7 d 8-
D
<30 wk >30 wk <24 hr 1-7 d 8-
Fetus
m: co-variates - age
3A4 “Switch”
0.15CYP3A4
ylat
ionCYP3A4
0.10
hydr
oxy
0.05 one
6β-h
0.05
stos
tero
-28 d 1-3 mo 3-12 mo >1 yr Adult0.00
Te
-28 d 1-3 mo 3-12 mo >1 yr Adult
Newborn
Page 34
drug metabolism
CYP2D6CYP2D6
Log M/M1
m: co-variates - age
CYP3A4CYP3A4
log M/M2
Page 35
drug metabolism
3 00
2,50
3,00
2,00
M2
ratio
1,00
1,50
/M1
or M
/M
0,50log
M
-0,50
0,0024 29 34 39 44 49
postmenstrual age (weeks)
m: co-variates - age
54 59
Page 36
drug metabolism
Bouwmeester et al,
m: co-variates - age
Br J Anaesth 2004
Page 37
drug metabolism
per kilogram
body surface
allometrics
m: relation to weight ?
kg 1
kg 0.65
kg 0.75
Page 38
drug metabolismm: relation to weight/age ?
Page 39
drug metabolismm: relation to weight ?
Page 40
drug metabolism
3,54
1 52
2,53
00,5
11,5
0
m: ontogeny and allometry
Clearance, l/h/kg (x10)
50 100 150 200 250 300
PNA (weeks)
Page 41
drug metabolismm: ontogeny and allometry
Page 42
drug metabolism: ontogeny and polymorphism
Page 43
drug metabolism: ontogeny and polymorphism
Page 45
drug metabolism:
3,0
2,5
2,0
1,5
1,0
0,5
0,0
log M/M1CYP2D6 = 1 alelle
ontogeny and polymorphism
log M/M1CYP2D6 = 2 alelles
Page 47
drug metabolism: ontogeny and polymorphism
Page 48
drug metabolism: ontogeny and polymorphism
Page 49
hepatic
Body compositionAge-dependent
Ref: Kearns e
renal
route dependent/bio-availability
et al, NEJM 2003
Page 50
renal drug elim
Néphrologie peri
mination
inatal, vol 4, p 39
Page 51
renal drug elim
GFR/postnatal age
50
60
40
20
30
0
10
00 5 10 15 20 2
Guignard et al, J Pediatr 1975
mination
GFR/gentamicin
100
12015 full term15 full term23 premature23 premature
80
100 23 premature23 premature
40
60
0
20
250
0 20 40 60 80 100 120
Koren et al, Clin Pharmacol Ther 1975
Page 52
renal drug elim
Biol Neonate 19
mination
998;74:351-62
Page 53
renal drug elimina
2
2.5CL individual place
CL population plac
1.5
2
0kg)
CL population plac
1
CL(l/
h/70
0.5
C
023 24 25 26
Post concePost conce
Br J Clin Pharmacol 20
ation: age and NSAID’s
ebo CL individual nsaid
cebo CL population nsaidcebo CL population nsaid
27 28 29 30 31
eption age (weeks)eption age (weeks)
006 (aminoglycosides)
Page 54
renal drug elimina
3 5
4CL individualCL population ibuprof
2,5
3
3,5
h/70
kg)
1,5
2
,
ance
(L/h
0,5
1
Clea
ra
020 25 3
P t tPostmenstrua
Br J Clin Pharmacol 2
ation: age and NSAID’s
CL populationfen CL ibuprofen
30 35 40
l ( k )al age (weeks)
2007 (glycopeptides)
Page 55
renal drug elimina
back to adthe Barker hypot
1 81,8
1,6
1 41,4
1,2
1 01,0
0,8
0,6
0,4
0,2
AGA SGA
Ther Drug
ation
dulthood…thesis confirmed
2 52,5
2,0
1,5
1,0
0,5
0,0
AGA SGA
Monit 2007
Page 56
Take home messages
unlicensed/off-label use of dru
Children are different
specific diseas
pathophysiolo
maturation
i t i di id linterindividual
ugs
ses
ogy
l i bilitl variability
Page 57
Neonatal Intensive Care UnGasthuisberg Leuven
Neonatal Intensive Care UG th i b LGasthuisberg, Leuven
V Cossey, A DebG Naulaers, M R
Gasthuisberg, LeuvenV Cossey, A DeG Naulaers, M
Center for Clinical PharmaGasthuisberg, Leuven
J de Hoon, R Ve
Center for Clinical PharmaGasthuisberg, Leuven
J de Hoon, R V
Eramus Medical Center, RoSophia’s Children’s Hospit
Eramus Medical Center, RSophia’s Children’s Hospit
D Tibboel, J vaD Tibboel, J van
Antwerp University Hospit
D Tibboel, J vaR van Schaik
Antwerp University HospitB van Overmeir
Neonatal Intensive Care UnJP Langhendrie
B van Overme
Neonatal Intensive Care UJP LanghendriJP Langhendrie
Pediatric Nephrology UnitDepartment of Paediatrics,
JP Langhendri
Pediatric Nephrology UnitDepartment of Paediatrics
JP Guignard
Department of AnaesthesioClinical Pharmacology
JP Guignard
Department of AnaesthesioClinical PharmacologyClinical Pharmacology
University Hospital, AucklaB Anderson, N H
Clinical PharmacologyUniversity Hospital, Auckl
B Anderson, N
nitnit
beer, H DevliegerRayyan, C Vanholeebeer, H Devlieger
M Rayyan, C Vanhole
acology
erbesselt
acology
Verbesselt
otterdamtal, the Netherlands
Rotterdamtal, the Netherlandsan den Ankern den Anker
al, Edegem
an den Anker
tal, Edegemre
nit, Rocourtes
ire
nit, Rocourtieses
, Lausanne
ies
, Lausanne
ology andology and
and, New ZealandHolfordland, New Zealand
N Holford