developmental clinical pharmacology on the use of drugs in ...

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

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

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

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 %

drug interactions

Br J Clin Pha

s

armacol 2006

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

neuro-anatomical

Ruda et al. Science 2000/

l changes: spinal cord

0/ Walker et al. Pain 2003

developmental nnephrology

from paediatricc life to adulthood

from adulthood bback to paediatrics

developmental p

dru

Dose Con

pharmacokinetics

harmacokinetics

ug

nc Effect

pharmacodynamics

hepatic

Body composition

Ref: Kearns et

renal

Formulation/bio-availability

t al, NEJM 2003

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

brain/body fracti

Ref: Nelson’s textbook

ion

k Pediatrics

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

hepatic

Body compositionAge-dependent

Ref: Kearns et

renal

Formula dependent

al, NEJM 2003

Ref: Rakhmanina et al, 2006

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

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

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

distribution volum

Biol Neonate 19

me: hydrophylic drugs

998;74:351-62

hepatic


Ref: Kearns e

renal

route dependent/bio-availability

et al, NEJM 2003

gastro-intestinaal track/bio-availability

gastro-intestinaal track/bio-availability

Rectal route

Oral route

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

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)

hepatic


Ref: Kearns e

renal


et al, NEJM 2003

Ref: Weinshilbouum, NEJM 2003

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

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

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

drug metabolism

CYP2D6CYP2D6

Log M/M1


CYP3A4CYP3A4

log M/M2

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)


54 59

drug metabolism

Bouwmeester et al,


Br J Anaesth 2004

drug metabolism

per kilogram

body surface

allometrics

m: relation to weight ?

kg 1

kg 0.65

kg 0.75

drug metabolismm: relation to weight/age ?

drug metabolismm: relation to weight ?

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)

drug metabolismm: ontogeny and allometry

drug metabolism: ontogeny and polymorphism

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

drug metabolism: ontogeny and polymorphism

hepatic


Ref: Kearns e

renal


et al, NEJM 2003

renal drug elim

Néphrologie peri

mination

inatal, vol 4, p 39

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

renal drug elim

Biol Neonate 19

mination

998;74:351-62

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)

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)

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

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

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

developmental clinical pharmacology on the use of drugs in ...

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