Developmental PharmacologyDevelopmental PharmacologyDevelopmental PharmacologyDevelopmental PharmacologyScaling adult doses to infants based on body Scaling adult doses to infants based on body weight or surface area does not account for weight or surface area does not account for

developmental changes that affect drug developmental changes that affect drug disposition or tissue/organ sensitivity.disposition or tissue/organ sensitivity.

Scaling adult doses to infants based on body Scaling adult doses to infants based on body weight or surface area does not account for weight or surface area does not account for

developmental changes that affect drug developmental changes that affect drug disposition or tissue/organ sensitivity.disposition or tissue/organ sensitivity.

ChloramphenicolChloramphenicol

Natural product of Natural product of StreptomycesStreptomyces (1947) (1947)

Inhibits protein synthesis (bacteriostatic)Inhibits protein synthesis (bacteriostatic)

Eliminated by glucuronide conjugation (90%) and Eliminated by glucuronide conjugation (90%) and renal excretion (<10%)renal excretion (<10%)

Nursery infections treated with high dosesNursery infections treated with high doses

O2N

NCl

Cl

O

OHH

H

OHO2N

NCl

Cl

O

OHH

H

OH

Chloramphenicol in InfantsChloramphenicol in Infants

3320 gm infant, 44 week gestation3320 gm infant, 44 week gestation

Meconium stained, foul smelling, timing of ROM Meconium stained, foul smelling, timing of ROM unknownunknown

Procaine penicillin (50,00 units) + chloramphenicol Procaine penicillin (50,00 units) + chloramphenicol (250 mg) IM q8h - 230 mg/kg/day x 72 hr(250 mg) IM q8h - 230 mg/kg/day x 72 hr

Day 4, gray color & cold, moist skinDay 4, gray color & cold, moist skin

Died at 106 hr, 8 hr after onset of vascular collapseDied at 106 hr, 8 hr after onset of vascular collapse

Sutherland, Am J Dis Child 97:761-7, 1959Sutherland, Am J Dis Child 97:761-7, 1959

Chloramphenicol in Premature InfantsChloramphenicol in Premature Infants

All Infants 2001-2500 gm

n Deaths n Deaths

No antibiotics 32 6 17 1

Pen + strep 33 6 24 0

Chloramphenicol 30 19 16 8

Pen + strep +chloramphenicol 31 21 15 6

All Infants 2001-2500 gm

n Deaths n Deaths

No antibiotics 32 6 17 1

Pen + strep 33 6 24 0

Chloramphenicol 30 19 16 8

Pen + strep +chloramphenicol 31 21 15 6

Burns et al., NEJM 261:1318-21, 1959Burns et al., NEJM 261:1318-21, 1959

Premature infants born ≥24 hrs after ROMPremature infants born ≥24 hrs after ROM

Gray Baby SyndromeGray Baby Syndrome

0 10 20 30 40 50 60 70 80

No AntibioticsPen + StrepChloramphenicol

0 10 20 30 40 50 60 70 80

No AntibioticsPen + StrepChloramphenicol

% of Infants% of Infants

JaundiceJaundice

VomitingVomiting

AnorexiaAnorexia

Resp. distressResp. distress

Abd. distentionAbd. distention

CyanosisCyanosis

Green stoolsGreen stools

LethargyLethargy

Ashen colorAshen color

DeathDeath

44

4.14.1

4.34.3

4.54.5

4.64.6

4.74.7

55

5.35.3

5.75.7

Burns et al., NEJM 261:1318-21, 1959Burns et al., NEJM 261:1318-21, 1959

Chloramphenicol Blood LevelsChloramphenicol Blood Levels

0

50

100

150

200

0 1 2 3 40

50

100

150

200

0 1 2 3 4

Day of LifeDay of Life

Total Nitro Total Nitro Compounds Compounds

[µg/ml][µg/ml]

Therapeutic rangeTherapeutic range

Chloramphenicol dosesChloramphenicol doses

Burns et al., NEJM 261:1318-21, 1959Burns et al., NEJM 261:1318-21, 1959

Chloramphenicol PharmacokineticsChloramphenicol Pharmacokinetics

Weiss et al., NEJM 262:787-94, 1960Weiss et al., NEJM 262:787-94, 1960

4

6

810

30

50

0 12 24 36 48 60

4

6

810

30

50

0 12 24 36 48 60

Time [hr]Time [hr]

Total Nitro Total Nitro Compounds Compounds

[µg/ml][µg/ml]

4-5 yrs. (n=3)4-5 yrs. (n=3)

1-2 days (n=5)1-2 days (n=5)

10-16 days (n=3)10-16 days (n=3)tt1/21/2 - 26 hrs - 26 hrs

tt1/21/2 - 4 hrs - 4 hrs

tt1/21/2 - 10 hrs - 10 hrs

Repeated AdministrationRepeated Administration

0

5

10

15

20

25

30

0 5 10 15 20 25 300

5

10

15

20

25

30

0 5 10 15 20 25 30

Weiss et al., NEJM 262:787-94, 1960Weiss et al., NEJM 262:787-94, 1960

Day of LifeDay of Life

Total Nitro Total Nitro Compounds Compounds

[µg/ml][µg/ml]

Drug Use in Infants and ChildrenDrug Use in Infants and Children

Scaling adult doses based on body weight or Scaling adult doses based on body weight or surface area does not account for developmental surface area does not account for developmental changes that affect drug disposition or changes that affect drug disposition or tissue/organ sensitivity.tissue/organ sensitivity.

Pharmacologic impact of developmental changes Pharmacologic impact of developmental changes are often discovered when unexpected or severe are often discovered when unexpected or severe toxicity in infants and children leads to detailed toxicity in infants and children leads to detailed pharmacologic studies.pharmacologic studies.

Therapeutic tragedies could be avoided by Therapeutic tragedies could be avoided by performing pediatric pharmacologic studies performing pediatric pharmacologic studies during the drug development process (before during the drug development process (before wide-spread use of agents in infants and wide-spread use of agents in infants and children).children).

ZidovudineZidovudine

Synthetic nucleoside analogSynthetic nucleoside analog

Inhibits HIV reverse transcriptaseInhibits HIV reverse transcriptase

Eliminated by glucuronide conjugation (67%) and Eliminated by glucuronide conjugation (67%) and renal excretion (33%)renal excretion (33%)

Perinatal therapy to prevent HIV transmissionPerinatal therapy to prevent HIV transmission

O

O

O

CH3HN

NHOCH2

N3

O

O

O

CH3HN

NHOCH2

N3

Zidovudine in the NewbornZidovudine in the Newborn

0

1

2

3

4

5

6

7

0.1 1 100

1

2

3

4

5

6

7

0.1 1 10

Age [weeks]Age [weeks]

ZDV AUC ZDV AUC [µg•hr/ml][µg•hr/ml]

Boucher et al., J Pediatr 122:137-44, 1993Boucher et al., J Pediatr 122:137-44, 1993

Zidovudine in NewbornsZidovudine in Newborns

Boucher et al., J Pediatr 125:642-9, 1994Boucher et al., J Pediatr 125:642-9, 1994Mirochnick et al., Antimicrob Agents Chemother 42:808-12, 1998Mirochnick et al., Antimicrob Agents Chemother 42:808-12, 1998

Balis et al., J Pediatr 114:880-4, 1989Balis et al., J Pediatr 114:880-4, 1989Klecker et al., Clin Pharmacol Ther 41: 407-12, 1987Klecker et al., Clin Pharmacol Ther 41: 407-12, 1987

Prevention of HIV TransmissionPrevention of HIV Transmission

0 3 6 9 12 15 18

0

1

2

3

6

12

Hemoglobin [g/dl]Hemoglobin [g/dl]

Age Age [weeks][weeks]

ZidovudineZidovudinePlaceboPlacebo

Connor et al., NEJM 331:1173-80, 1994Connor et al., NEJM 331:1173-80, 1994

Ontogeny and PharmacologyOntogeny and Pharmacology

Excretory organ (liver and kidneys) development Excretory organ (liver and kidneys) development has the greatest impact on drug disposition has the greatest impact on drug disposition (pharmacokinetics)(pharmacokinetics)

The most dramatic changes occur during the first The most dramatic changes occur during the first days to months of lifedays to months of life

Anticipate age-related differences in drug Anticipate age-related differences in drug disposition based on knowledge of ontogenydisposition based on knowledge of ontogeny

Effect of ontogeny on tissue/organ sensitivity to Effect of ontogeny on tissue/organ sensitivity to drugs (pharmacodynamics) is poorly studieddrugs (pharmacodynamics) is poorly studied

Disease states may alter a drug’s PK/PDDisease states may alter a drug’s PK/PD

Glomerular filtration rateGlomerular filtration rate• Low at birthLow at birth

• Full term newborn - 10-15 ml/min/mFull term newborn - 10-15 ml/min/m22

• Premature - 5-10 ml/min/mPremature - 5-10 ml/min/m22

• GFR doubles by 1 week of ageGFR doubles by 1 week of age

• Adult values by 6-12 months of ageAdult values by 6-12 months of age

Tubular functionTubular function• Secretory function impaired at birthSecretory function impaired at birth

• Glomerulotubular imbalanceGlomerulotubular imbalance

• Adult values by 1 year of ageAdult values by 1 year of age

Renal OntogenyRenal Ontogeny

Glomerular Filtration RateGlomerular Filtration Rate

0

20

40

60

80

100

120

140

160

0 2 4 6 8 10 12 140

20

40

60

80

100

120

140

160

0 2 4 6 8 10 12 14

GFR GFR [ml/min/1.73 m[ml/min/1.73 m22]]

Age [months]Age [months]

Aperia, Acta Pædiatr Scand 64:393-8, 1975Aperia, Acta Pædiatr Scand 64:393-8, 1975

0

10

20

30

40

50

60

0 5 10 15 20 250

10

20

30

40

50

60

0 5 10 15 20 25

GFR in InfantsGFR in Infants

GFR GFR [ml/min/1.73 m[ml/min/1.73 m22]]

Age [days]Age [days]

Guignard, J Pediatr 87:268-72, 1975Guignard, J Pediatr 87:268-72, 1975

Gentamicin in the NewbornGentamicin in the Newborn

0

20

40

60

80

100

120

0 20 40 60 80 100 1200

20

40

60

80

100

120

0 20 40 60 80 100 120

Gentamicin Gentamicin Clearance Clearance [ml/kg•hr][ml/kg•hr]

Creatinine Clearance [ml/kg•hr]Creatinine Clearance [ml/kg•hr]

15 full term15 full term

23 premature23 premature

Koren et al., Clin Pharmacol Ther 38:680-5, 1985Koren et al., Clin Pharmacol Ther 38:680-5, 1985

0.04 0.06 0.08 0.1 0.12

0-2 days

3-7 days

8 days

0.04 0.06 0.08 0.1 0.12

0-2 days

3-7 days

8 days

Gentamicin ClearanceGentamicin Clearance

Postnatal Postnatal AgeAge

Gentamicin Clearance [L/kg•hr]Gentamicin Clearance [L/kg•hr]

Premature (<37 weeks)Premature (<37 weeks)

Full termFull term

Pons, Ther Drug Monit 10:421-7, 1988Pons, Ther Drug Monit 10:421-7, 1988

Phase 1 Phase 1 (oxidation, hydrolysis, reduction, demethylation)(oxidation, hydrolysis, reduction, demethylation)

• Activity low at birthActivity low at birth

• Mature at variable ratesMature at variable rates• Oxidative metabolism increases rapidly after birthOxidative metabolism increases rapidly after birth• Alcohol dehydrogenase reaches adult levels at 5 yrsAlcohol dehydrogenase reaches adult levels at 5 yrs

• Activity in young children exceeds adult levelsActivity in young children exceeds adult levels

Phase 2Phase 2 (conjugation, acetylation, methylation)(conjugation, acetylation, methylation)

• Conjugation:Conjugation:• Glucuronidation Glucuronidation at birthat birth• Sulfatation Sulfatation at birth at birth

• Acetylation Acetylation at birth, “fast” or “slow” phenotype at birth, “fast” or “slow” phenotype by 12-15 mo.by 12-15 mo.

Hepatic OntogenyHepatic Ontogeny

Cytochrome P450 (CYP) EnzymesCytochrome P450 (CYP) Enzymes

Superfamily of Phase 1 enzymes (oxidation, Superfamily of Phase 1 enzymes (oxidation, demethylation)demethylation)

Nomenclature:Nomenclature:

17 Families and 39 subfamilies in humans17 Families and 39 subfamilies in humans

CYP1, CYP2, CYP3 are primary drug metabolizing CYP1, CYP2, CYP3 are primary drug metabolizing enzymesenzymes

Half of all drugs metabolized by CYP3A subfamilyHalf of all drugs metabolized by CYP3A subfamily

CYP3A4 is most abundant hepatic P450 enzyme CYP3A4 is most abundant hepatic P450 enzyme and metabolizes at least 50 drugsand metabolizes at least 50 drugs

CYP3A4CYP3A4Family (>40%)Family (>40%) Subfamily (>55%)Subfamily (>55%)

IsoformIsoform

Cytochrome P450 EnzymesCytochrome P450 Enzymes

PRESENT IN FETUS

APPEAR AFTER

BIRTH

APPEAR 3-4MONTHS OF AGE

CYP3A7* CYP2D6 CYP1A2

CYP1A1 CYP3A4*

CYP3A5 CYP2C9

CYP2C18/19

CYP2E1

* Most abundant form

PRESENT IN FETUS

APPEAR AFTER

BIRTH

APPEAR 3-4MONTHS OF AGE

CYP3A7* CYP2D6 CYP1A2

CYP1A1 CYP3A4*

CYP3A5 CYP2C9

CYP2C18/19

CYP2E1

* Most abundant form

CYP3A OntogenyCYP3A Ontogeny

0

0.5

1

1.5

0

0.05

0.1

0.15

0

0.5

1

1.5

0

0.05

0.1

0.15

<3

0w

<3

0w

>3

0w

>3

0w

<2

4h

<2

4h

1-7

d1-7

d

8-2

8d

8-2

8d

1-3

mo

1-3

mo

3-1

2m

o3-1

2m

o

>1

yr

>1

yr

Adult

Adult

FetusFetusPostnatal AgePostnatal Age

CYP3A7 CYP3A7 ActivityActivity

CYP3A4 CYP3A4 ActivityActivity

LaCroix D et al. Eur J Biochem 247:625, 1997LaCroix D et al. Eur J Biochem 247:625, 1997

0.30.3

0.750.75

1.61.6

1.81.8

G:SG:S

Acetaminophen MetabolismAcetaminophen Metabolism

0 20 40 60 80 100

Newborn

3-9 years

12 years

Adults

AcetaminophenGlucuronideSulfate

0 20 40 60 80 100

Newborn

3-9 years

12 years

Adults

AcetaminophenGlucuronideSulfate

Miller et al., Clin Pharmacol Ther 19:284-94, 1976Miller et al., Clin Pharmacol Ther 19:284-94, 1976

0.150.15

0.170.17

0.190.19

0.180.18

kkelel

% of Dose% of Dose

Theophylline Urinary MetabolitesTheophylline Urinary Metabolites

0 20 40 60 80 100

28-32 weeks

40-50 weeks

2-3 years

4-9 years

10-16 years

TheophyllineCaffiene3-MeX1-MeUA1,3-diMeUA

0 20 40 60 80 100

28-32 weeks

40-50 weeks

2-3 years

4-9 years

10-16 years

TheophyllineCaffiene3-MeX1-MeUA1,3-diMeUA

% Recovered in Urine% Recovered in Urine

Post-Post-conception conception

AgeAge

Age Age RangeRange

Clearance Clearance [ml/min/kg][ml/min/kg]

2020

7070

100100

Factors Affecting Drug DistributionFactors Affecting Drug Distribution

Physicochemical properties of the drugPhysicochemical properties of the drug

Cardiac output/Regional blood flowCardiac output/Regional blood flow

Degree of protein/tissue bindingDegree of protein/tissue binding

Body compositionBody composition

• Extracellular waterExtracellular water

• Adipose tissueAdipose tissue

Ontogeny of Body CompositionOntogeny of Body Composition

% of Total Body Weight% of Total Body Weight

EC HEC H22OO IC HIC H22OO

ProteinProtein OtherOther

FatFat

0 20 40 60 80 100

Premature

Newborn

4 mo

12 mo

24 mo

36 mo

Adult

0 20 40 60 80 100

Premature

Newborn

4 mo

12 mo

24 mo

36 mo

Adult

Kaufman, Pediatric Pharmacology (Yaffe & Aranda, eds) pp. 212-9, 1992Kaufman, Pediatric Pharmacology (Yaffe & Aranda, eds) pp. 212-9, 1992

Volume of Distribution of SulfaVolume of Distribution of Sulfa

0 0.1 0.2 0.3 0.4 0.5

Newborn

Infant

Children

Adults

Elderly

0 0.1 0.2 0.3 0.4 0.5

Newborn

Infant

Children

Adults

Elderly

Volume of Distribution [L/kg]Volume of Distribution [L/kg]

Routledge, J Antimicrob Chemother 34 Suppl A:19-24, 1994Routledge, J Antimicrob Chemother 34 Suppl A:19-24, 1994

Tissue and Organ WeightTissue and Organ Weight

% of Total Body Weight

Fetus Newborn Adult

Skeletal muscle 25 25 40

Skin 13 4 6

Skeleton 22 18 14

Heart 0.6 0.5 0.4

Liver 4 5 2

Kidneys 0.7 1 0.5

Brain 13 12 2

% of Total Body Weight

Fetus Newborn Adult

Skeletal muscle 25 25 40

Skin 13 4 6

Skeleton 22 18 14

Heart 0.6 0.5 0.4

Liver 4 5 2

Kidneys 0.7 1 0.5

Brain 13 12 2

% of Total Body Weight

Fetus Newborn Adult

Skeletal muscle 25 25 40

Skin 13 4 6

Skeleton 22 18 14

Heart 0.6 0.5 0.4

Liver 4 5 2

Kidneys 0.7 1 0.5

Brain 13 12 2

% of Total Body Weight

Fetus Newborn Adult

Skeletal muscle 25 25 40

Skin 13 4 6

Skeleton 22 18 14

Heart 0.6 0.5 0.4

Liver 4 5 2

Kidneys 0.7 1 0.5

Brain 13 12 2

Plasma ProteinsPlasma Proteins

Change from Adult Values

Newborn Infant Child

Total protein

Albumin

1-Acid glycoprotein

Fetal albumin Present Absent Absent

Globulin

Change from Adult Values

Newborn Infant Child

Total protein

Albumin

1-Acid glycoprotein

Fetal albumin Present Absent Absent

Globulin

Protein Binding in Cord and Adult PlasmaProtein Binding in Cord and Adult Plasma

Kurz et al., Europ J Clin Pharmacol II:463-7, 1977Kurz et al., Europ J Clin Pharmacol II:463-7, 1977

30.230.2 17.317.3

CSF MTX and AgeCSF MTX and Age

0.001

0.01

0.1

1

10

1 2 3 4 5 6 7 8 9

AdultsAdolescentsChildren

0.001

0.01

0.1

1

10

1 2 3 4 5 6 7 8 9

AdultsAdolescentsChildren

Time [days]Time [days]

CSF Methotrexate

[µM]

CSF Methotrexate

[µM]

Bleyer, Cancer Treat Rep 61:1419-25, 1977Bleyer, Cancer Treat Rep 61:1419-25, 1977

CNS Growth and DevelopmentCNS Growth and Development

Birth 4 8 12 16 20 24

20

40

60

80

100

Birth 4 8 12 16 20 24

20

40

60

80

100

Age [yrs]Age [yrs]

Adult Value [%]

Adult Value [%]

CNS VolumeCNS Volume

Body Surface AreaBody Surface Area

Bleyer, Cancer Treat Rep 61:1419-25, 1977Bleyer, Cancer Treat Rep 61:1419-25, 1977

Adaptive IT MTX Dosing RegimenAdaptive IT MTX Dosing Regimen

Bleyer, Cancer Treat Rep 61:1419-25, 1977Bleyer, Cancer Treat Rep 61:1419-25, 1977

Dose Change with Adaptive RegimenDose Change with Adaptive Regimen

0

-25

+25

+50

+75

1.5 4 7 10 13

0

-25

+25

+50

+75

1.5 4 7 10 13

Age [yrs]Age [yrs]

% Change in Dose

% Change in Dose

Adaptive doseAdaptive dose12 mg/m2 dose12 mg/m2 dose

X 100X 100

Bleyer, J Clin Oncol 1:317-25, 1983Bleyer, J Clin Oncol 1:317-25, 1983

Effect of Adaptive IT Dosing on OutcomeEffect of Adaptive IT Dosing on Outcome

Incidence ofCNS Relapse

[%]

Incidence ofCNS Relapse

[%]

MTX Dose Based on BSAMTX Dose Based on BSA

MTX Dose Based on AgeMTX Dose Based on Age

Age [months]Age [months]

ConcurrentConcurrent

IsolatedIsolated

00

1010

00

1010

2020

<18<18 18-3518-35

36-8336-83

84-11984-119

≥12≥12

Bleyer, J Clin Oncol 1:317-25, 1983Bleyer, J Clin Oncol 1:317-25, 1983

Body Weight :Surface AreaBody Weight :Surface Area

0

5

10

15

20

25

30

35

40

0 5 10 15 20 250

5

10

15

20

25

30

35

40

0 5 10 15 20 25

Age [yrs]Age [yrs]

WeightWeight

BSABSA

AdultAdult

1 mg/kg = 40 mg/m1 mg/kg = 40 mg/m22

Dose = 70 mgDose = 70 mg

1 y.o.1 y.o.

1 mg/kg = 10 mg1 mg/kg = 10 mg

40 mg/m40 mg/m22 = 18 mg = 18 mg

Anticancer Drug ClearanceAnticancer Drug Clearance

McLeod et al., Br J Cancer 66 (Suppl. 18):S23-S29, 1992McLeod et al., Br J Cancer 66 (Suppl. 18):S23-S29, 1992

DRUG

ROUTE OF

ELIMINATION

CLINFANTS VS

CLCHILDREN DOSING

Methotrexate R (15%) No adjustments

Mercaptopurine M ND No adjustments

Vincristine M (/m2) <1 yo, dose/kg

VM26/VP16 M ND (/m2) No adjustments (/m2)

Doxorubicin B, M (/m2) <2 yo, dose/kg or Êdose/m2

Cytarabine M ND No adjustment

DRUG

ROUTE OF

ELIMINATION

CLINFANTS VS

CLCHILDREN DOSING

Methotrexate R (15%) No adjustments

Mercaptopurine M ND No adjustments

Vincristine M (/m2) <1 yo, dose/kg

VM26/VP16 M ND (/m2) No adjustments (/m2)

Doxorubicin B, M (/m2) <2 yo, dose/kg or Êdose/m2

Cytarabine M ND No adjustment

Vincristine ClearanceVincristine Clearance

0 100 200 300 400 500

Infants

Children

Adolescents

0 100 200 300 400 500

Infants

Children

Adolescents

0 5 10 15 20 25

Infants

Children

Adolescents

0 5 10 15 20 25

Infants

Children

Adolescents

Vincristine Clearance Vincristine Clearance [ml/min/[ml/min/mm22]]

Vincristine Clearance Vincristine Clearance [ml/min/[ml/min/kgkg]]

Crom et al., J Pediatr 125:642-9, 1994Crom et al., J Pediatr 125:642-9, 1994

Etoposide ClearanceEtoposide Clearance

0

5

10

15

20

25

30

p = 0.5

<1 yr(n=5)

>1 yr(n=25)

0

5

10

15

20

25

30

p = 0.5

<1 yr(n=5)

>1 yr(n=25)

<1 yr(n=5)

>1 yr(n=25)

p = 0.004

0

1.2

0.8

0.4

<1 yr(n=5)

>1 yr(n=25)

p = 0.004

0

1.2

0.8

0.4

EtoposideEtoposideClearanceClearance

[ml/min/[ml/min/mm22]]

EtoposideEtoposideClearanceClearance[ml/min/[ml/min/kgkg]]

Doxorubicin ClearanceDoxorubicin Clearance

10

20

30

40

50

60

70

80

90

<2 yr(n=8)

>2 yr(n=52)

p = 0.39

10

20

30

40

50

60

70

80

90

<2 yr(n=8)

>2 yr(n=52)

p = 0.39

0

500

1000

1500

2000

2500

<2 yr(n=8)

>2 yr(n=52)

p = 0.015

0

500

1000

1500

2000

2500

<2 yr(n=8)

>2 yr(n=52)

p = 0.015

DoxorubicinDoxorubicinClearanceClearance

[ml/min/[ml/min/mm22]]

DoxorubicinDoxorubicinClearanceClearance[ml/min/[ml/min/kgkg]]

Oral Busulfan (16-30 mg/kg)Oral Busulfan (16-30 mg/kg)

0

200

400

600

800

1000

1200

1400

0 10 20 30 40 50 600

200

400

600

800

1000

1200

1400

0 10 20 30 40 50 60

EngraftmentEngraftment

Graft rejectionGraft rejection

Age [yrs]Age [yrs]

Busulfan CBusulfan Cssss

[ng/ml][ng/ml]

Slattery et al., Bone Marrow Transplant 16:31, 1995Bone Marrow Transplant 16:31, 1995

Drug Clearance in Cystic FibrosisDrug Clearance in Cystic Fibrosis

0 20 40 60 80 100 120 140

Gentamycin

Ticarcillin

Ceftazidime

Cloxacillin (NR)

Theophylline

Furosemide (NR)

Ibuprofen

0 20 40 60 80 100 120 140

Gentamycin

Ticarcillin

Ceftazidime

Cloxacillin (NR)

Theophylline

Furosemide (NR)

Ibuprofen

Clearance [ml/min•m2]Clearance [ml/min•m2]

Ren

alR

enal

Hep

aticH

epatic

Rey, Clin Pharmacokinet 35:313-29, 1998Rey, Clin Pharmacokinet 35:313-29, 1998

Cystic FibrosisCystic FibrosisControlsControls

RetinoidsRetinoids

≤≤12 Yr.12 Yr. >12 Yr>12 Yr AdultAdult

ATRAATRA

MTDMTD 60 mg/m60 mg/m22/d/d 90 mg/m90 mg/m22/d/d 150 mg/m150 mg/m22/d/d

DLTDLT Pseudotumor Pseudotumor cerebricerebri

HA and PCHA and PC DermatologicDermatologic

9-cis-RA9-cis-RA

MTDMTD 35 mg/m35 mg/m22/d/d 85 mg/m85 mg/m22/d/d 140 mg/m140 mg/m22/d/d

DLTDLT Pseudotumor Pseudotumor cerebricerebri

HA and PCHA and PC HA, diarrhea, HA, diarrhea, dermatologicdermatologic

ConclusionsConclusions

Infants (esp. newborns) may have reduced Infants (esp. newborns) may have reduced capacity to eliminate drugscapacity to eliminate drugs

Anticipate the effects of ontogeny on drug Anticipate the effects of ontogeny on drug disposition based on route of eliminationdisposition based on route of elimination

More systematic pharmacokinetic studies More systematic pharmacokinetic studies of anticancer drugs in infants are neededof anticancer drugs in infants are needed

Tissue sensitivity to the toxic effects of Tissue sensitivity to the toxic effects of anticancer drugs may be age-dependentanticancer drugs may be age-dependent

THE ENDTHE END