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

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

Frank Balis, M.D.Frank Balis, M.D.February 22, 2007February 22, 2007

ChloramphenicolChloramphenicol

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

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

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

• Nursery infections treated with high dosesNursery infections treated with high doses

O2N

NCl

Cl

O

OHH

HOH

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 (250 Procaine penicillin (50,00 units) + chloramphenicol (250 mg) IM q8h - 230 mg/kg/day x 72 hrmg) 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, 1959

Chloramphenicol in Premature InfantsChloramphenicol in Premature Infants

All Infants 2001-2500 gmn Deaths n Deaths

No antibiotics 32 6 17 1Pen + strep 33 6 24 0

Chloramphenicol 30 19 16 8Pen + 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

% 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 4Day 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, 1959

Chloramphenicol PharmacokineticsChloramphenicol Pharmacokinetics

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

4

68

10

30

50

0 12 24 36 48 60Time [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 30

Weiss et al., NEJM 262:787-94, 1960Day 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 surface Scaling adult doses based on body weight or surface area does not account for developmental changes that area does not account for developmental changes that affect drug disposition or tissue/organ sensitivity.affect drug disposition or tissue/organ sensitivity.

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

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

ZidovudineZidovudine

• Synthetic nucleoside analogSynthetic nucleoside analog

• Inhibits HIV reverse transcriptaseInhibits HIV reverse transcriptase

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

• Perinatal therapy to prevent HIV transmissionPerinatal therapy to prevent HIV transmission

O

O

O

CH3HN

NHOCH2

N3

Zidovudine in the NewbornZidovudine in the Newborn

0

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

• The most dramatic changes occur during the The most dramatic changes occur during the first days to months of lifefirst days 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 14

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

Age [months]Age [months]Aperia, Acta Pædiatr Scand 64:393-8, 1975

0

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 80 100 120

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

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

15 full term15 full term23 premature23 premature

Koren 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

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

Hepatic OntogenyHepatic Ontogeny

Cytochrome P450 (CYP) EnzymesCytochrome P450 (CYP) Enzymes

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

• Nomenclature:Nomenclature:

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

• CYP1, CYP2, CYP3 are primary drug metabolizing enzymesCYP1, CYP2, CYP3 are primary drug metabolizing enzymes

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

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

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

IsoformIsoform

CYP OntogenyCYP Ontogeny

0

30

60

90

120

150

180

<24

hr

1-7

days

8-28

day

s

1-3

mo

3-12

mo

1-10

yr

Ontogeny of CYP Enzymes

CYP3A4CYP1A2CYP2D6UGT2B7

Perc

ent A

dult

Act

ivity

Kearns GL et al. NEJM 349: 1157, 2003Kearns GL et al. NEJM 349: 1157, 2003

CYP2E1 Ontogeny

0

20

40

60

80

100

3rd

trim

este

r

0-30

day

s

31-9

0 da

ys

91 d

-18

yr

CYP2E1 Ontogeny

CY

P2E

1 [%

Adu

lt L

evel

]

CYP3A OntogenyCYP3A Ontogeny

0

0.5

1

1.5

0

0.05

0.1

0.15

<30w<30w>30w>30w<24h<24h1-7d1-7d8-28d8-28d1-3m

o1-3m

o3-12m

o3-12m

o>1yr>1yrAdultAdult

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

Miller 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

% 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 H22OOProteinProtein OtherOther

FatFat

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

Volume of Distribution [L/kg]Volume of Distribution [L/kg]Routledge, J Antimicrob Chemother 34 Suppl A:19-24, 1994

Tissue and Organ WeightTissue and Organ Weight

% of Total Body WeightFetus Newborn Adult

Skeletal muscle 25 25 40Skin 13 4 6

Skeleton 22 18 14Heart 0.6 0.5 0.4Liver 4 5 2

Kidneys 0.7 1 0.5Brain 13 12 2

% of Total Body WeightFetus Newborn Adult

Skeletal muscle 25 25 40Skin 13 4 6

Skeleton 22 18 14Heart 0.6 0.5 0.4Liver 4 5 2

Kidneys 0.7 1 0.5Brain 13 12 2

Plasma ProteinsPlasma Proteins

Change from Adult ValuesNewborn Infant Child

Total protein

Albumin

1-Acid glycoprotein

Fetal albumin Present Absent AbsentGlobulin

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

Kurz 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

Time [days]

CSF Methotrexate

[µM]

Bleyer, 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

Age [yrs]

Adult Value

[%]

CNS Volume

Body Surface Area

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

Adaptive IT MTX Dosing RegimenAdaptive IT MTX Dosing Regimen

Bleyer, 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 13Age [yrs]

% Change in Dose

Adaptive dose12 mg/m2 dose X 100

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

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

Incidence ofCNS Relapse

[%]

MTX Dose Based on BSA

MTX Dose Based on Age

Age [months]

Concurrent

Isolated

0

10

0

10

20

<18 18-35

36-83

84-119

≥12

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

Dosing Based on Body Surface AreaDosing Based on Body Surface Area• BSA = 2-dimensional surface area of the skinBSA = 2-dimensional surface area of the skin

• Estimated from formulas using weight & heightEstimated from formulas using weight & height

• Correlation between BSA and kidney/liver Correlation between BSA and kidney/liver function is weakfunction is weak

• BSA dosing evolved from scaling doses from BSA dosing evolved from scaling doses from animals to humans (toxicology)animals to humans (toxicology)

SpeciesSpecies Wt [kg]Wt [kg] BSA [mBSA [m22]] Dose [mg]Dose [mg] Dose [mg/kg]Dose [mg/kg] Dose [mg/mDose [mg/m22]]MouseMouse 0.0180.018 0.00750.0075 0.0270.027 1.51.5 3.63.6

RatRat 0.250.25 0.0450.045 0.1250.125 0.50.5 2.82.8

InfantInfant 88 0.40.4 1.251.25 0.150.15 3.13.1

ChildChild 2020 0.80.8 2.52.5 0.120.12 3.13.1

AdultAdult 7070 1.851.85 5.05.0 0.070.07 2.72.7

Pinkel, Cancer Res 18:853, 1958Pinkel, Cancer Res 18:853, 1958

Liver Function (Children)Liver Function (Children)

Murry et al. Drug Metab Disp 23:1110, 1995Murry et al. Drug Metab Disp 23:1110, 1995

400

600

800

1000

1200

1400

1600

1800

0.5 1 1.5 2

BSA [mBSA [m22]]

Liver Vol Liver Vol [ml][ml]

rr22=0.75=0.750

10

20

30

40

50

0.5 1 1.5 2

AP CL AP CL [ml/min][ml/min]

rr22=0.04=0.04

Excretory Organ GrowthExcretory Organ Growth

Age [yr]Age [yr]

Liver Liver [g][g]

Kidney Kidney [g/m[g/m22]]

Kidney Kidney [g/kg][g/kg]

Kidney Kidney [g][g]

Liver Liver [g/m[g/m22]]

Liver Liver [g/kg][g/kg]

0

500

1000

1500

0

50

100

150

200

250

300

0 3 6 9 12 15 18400

500

600

700

800

900

115

120

125

130

135

140

145

150

155

0 3 6 9 12 15 1820

25

30

35

3

4

5

6

7

0 3 6 9 12 15 18

Body Weight :Surface AreaBody Weight :Surface Area

0

5

10

15

20

25

30

35

40

0 5 10 15 20 25Age [yrs]Age [yrs]

WeightWeightBSABSA

AdultAdult1 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

DRUGROUTE OF

ELIMINATIONCLINFANTS VSCLCHILDREN DOSING

Methotrexate R (15%) No adjustmentsMercaptopurine M ND No adjustments

Vincristine M (/m2) <1 yo, dose/kgVM26/VP16 M ND (/m2) No adjustments (/m2)

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

Cytarabine M ND No adjustment

Vincristine ClearanceVincristine Clearance

0 100 200 300 400 500

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)

<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

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 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

Clearance [ml/min•m2]

Renal

Hepatic

Rey, Clin Pharmacokinet 35:313-29, 1998

Cystic FibrosisControls

RetinoidsRetinoids

≤≤12 Yr.12 Yr. >12 Yr>12 Yr AdultAdultATRAATRA

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-RAMTDMTD 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, HA, diarrhea, 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 of More systematic pharmacokinetic studies of drugs in infants are neededdrugs in infants are needed

• Tissue sensitivity to the toxic effects of drugs Tissue sensitivity to the toxic effects of drugs may be age-dependentmay be age-dependent