karel allegaert, md phd uz leuven determinants of variability in disposition of exogenous compounds...

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)

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

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

compound Exposure

Response

AbsorptionDistribution

Receptor InteractionBiotransformation

Excretion

AbsorptionDistribution

Receptor InteractionBiotransformation

Excretion

environmental genetics

diseasegrowthmaturation

extensive interindividual variability

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

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 ?

hepatic

renalBody composition

Formula dependent

Ref: Kearns et al, NEJM 2003

Ref: Rakhmanina et al, 2006

body composition is age-dependent

drug metabolism: relation to weight/age ?

Ref: Nelson’s textbook Pediatrics

brain/body fraction

Biol Neonate 1998;74:351-62

distribution volume: hydrophylic drugs

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

distribution volume: lipophylic drugs

hepatic

renalBody composition

Formula dependent

Ref: Kearns et al, NEJM 2003

Ref: Weinshilboum, NEJM 2003

biotransformation

DrugPhase IPhase I

CYPsEsterases

Dehydrogenases

CYPsEsterases

Dehydrogenases

Phase IIPhase II

UGTsNATsSTsMTsGSTs

UGTsNATsSTsMTsGSTs

MetaboliteMetabolite

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

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

CYP2B6/3A434 %

UGT77 %

propofol clearance is metabolic clearance

High capacity, low specificity : glucuronidationLow capacity, high specificity: CYP2B6

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 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

Br J Anaesth 2007

hepatic

renalBody composition

Formula dependent

Ref: Kearns et al, NEJM 2003

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

Biol Neonate 1998;74:351-62

renal drug elimination

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

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

renal drug elimination: disease characteristics

Ref: Weinshilboum, NEJM 2003

extensive interindividual variability

Pattern recognitionage sizeco-medicationdisease characteristicspolymorphisms

improved predictability

collaborative efforts, ‘sized’ techniquespopulation pklow volume samples

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