Developmental Pharmacology - National Institutes of …cc.nih.gov/training/training/principles/slides/...Developmental Pharmacology Scaling adult doses to infants based on body weight

Developmental PharmacologyDevelopmental PharmacologyScaling adult doses to infants based on body weight Scaling adult doses to infants based on body weight or surface area does not account for developmental or surface area does not account for developmental changes that affect drug disposition or tissue/organ changes that affect drug disposition or tissue/organ

sensitivity.sensitivity.

Frank Balis, M.D.Frank Balis, M.D.February 19, 2009February 19, 2009

ChloramphenicolChloramphenicol

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

•• Inhibits protein synthesis (Inhibits protein synthesis (bacteriostaticbacteriostatic))

•• Eliminated by Eliminated by glucuronideglucuronide

conjugation (90%) 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


in Infantsin Infants

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

•• MeconiumMeconium

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

•• Procaine penicillin (50,00 units) + Procaine penicillin (50,00 units) + chloramphenicolchloramphenicol

(250 (250 mg) IM q8h mg) IM q8h --

230 mg/kg/day x 72 hr230 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


in Premature Infantsin 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 261:1318Burns et al., NEJM 261:1318--21, 195921, 1959

Premature infants born Premature infants born ≥≥24 hrs after ROM24 hrs after ROM

Gray Baby SyndromeGray Baby Syndrome

0 10 20 30 40 50 60 70 80

No AntibioticsPen + StrepChloramphenicol

% of Infants% of Infants

JaundiceJaundiceVomitingVomiting

AnorexiaAnorexia

Resp. distressResp. distressAbdAbd. distention. 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 261:1318Burns et al., NEJM 261:1318--21, 195921, 1959


Blood LevelsBlood Levels

0

50

100

150

200

0 1 2 3 4Day of LifeDay of Life

Total Nitro Total Nitro Compounds Compounds

[[µµg/ml]g/ml]

Therapeutic rangeTherapeutic range


dosesdoses

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


PharmacokineticsPharmacokinetics

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

Time [hr]Time [hr]


[[µµg/ml]g/ml]

44--5 yrs. (n=3)5 yrs. (n=3)

11--2 days (n=5)2 days (n=5)

1010--16 days (n=3)16 days (n=3) tt1/21/2

--

26 hrs26 hrs

tt1/21/2

--

4 hrs4 hrs

tt1/21/2

--

10 hrs10 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, 1960Weiss et al., NEJM 262:787-94, 1960Day of LifeDay of Life


[[µµg/ml]g/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 widedevelopment process (before wide--spread use of agents 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 Eliminated by glucuronideglucuronide

conjugation (67%) and conjugation (67%) and renal excretion (33%)renal excretion (33%)

•• PerinatalPerinatal

therapy to prevent HIV transmissiontherapy to prevent HIV transmission

O

O

O

CH3HN

NHOCH2

N3


in the Newbornin the Newborn

0

1

2

3

4

5

6

7

0.1 1 10

Age [weeks]Age [weeks]

ZDV AUC ZDV AUC [[µµgg••hr/ml]hr/ml]

Boucher et al., J Boucher et al., J PediatrPediatr

122:137122:137--44, 199344, 1993


in Newbornsin Newborns

GroupAge

(days)Clearance(ml/min/kg)

t1/2(hr)

F(%)

Preterm 5.5 2.5 7.217.7 4.4 4.4

Term ² 14 10.9 3.1>14 19.0 1.9

Age GroupClearance(ml/min/kg)

t1/2(hr)

F(%)

1-13 yrs 24 1.5 68Adults 21 1.1 63

Boucher et al., J Boucher et al., J PediatrPediatr

125:642125:642--9, 19949, 1994MirochnickMirochnick

et al., et al., AntimicrobAntimicrob

Agents Agents ChemotherChemother

42:80842:808--12, 199812, 1998Balis et al., J Balis et al., J PediatrPediatr

114:880114:880--4, 19894, 1989KleckerKlecker

et al., Clin et al., Clin PharmacolPharmacol

TherTher

41: 40741: 407--12, 198712, 1987

Prevention of Vertical TransmissionPrevention of Vertical Transmission

•• Randomized, doubleRandomized, double--blind, placebo controlled blind, placebo controlled trialtrial

•• Rate of vertical transmission was the primary Rate of vertical transmission was the primary endpointendpoint

•• ZidovudineZidovudine/placebo regimen/placebo regimen–– Mothers: 100 mg of ZDV Mothers: 100 mg of ZDV antepartumantepartum

orally, 5 orally, 5

times daily, and then continuous infusion of 1 times daily, and then continuous infusion of 1 mg/kg/hr during labor and deliverymg/kg/hr during labor and delivery

–– Infants: 2 mg/kg orally every 6 hours for 6 weeks, Infants: 2 mg/kg orally every 6 hours for 6 weeks, beginning 8beginning 8--12 hours after birth.12 hours after birth.

Prevention of HIV TransmissionPrevention of HIV Transmission

Zidovudine Placebo

AGE >32 WEEKS

Number 121 127HIV-infected 9 31

Rate (%) 7.4 24.4AGE ³ 1 YEAR

Number 83 89HIV-infected 7 20

Rate (%) 8.4 22.50 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 331:1173Connor et al., NEJM 331:1173--80, 199480, 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 ageAnticipate age--related differences in drug 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 (drugs (pharmacodynamicspharmacodynamics) is poorly studied) is poorly studied

•• Disease states may alter a drugDisease states may alter a drug’’s PK/PDs PK/PD

•• GlomerularGlomerular

filtration ratefiltration rate–– Low at birthLow at birth

••

Full term newborn Full term newborn --

1010--15 ml/min/m15 ml/min/m22

••

Premature Premature --

55--10 ml/min/m10 ml/min/m22

–– GFR doubles by 1 week of ageGFR doubles by 1 week of age–– Adult values by 6Adult values by 6--12 months of age12 months of age

•• Tubular functionTubular function–– SecretorySecretory

function impaired at birthfunction impaired at birth

–– GlomerulotubularGlomerulotubular

imbalanceimbalance–– Adult values by 1 year of ageAdult values by 1 year of age

Renal OntogenyRenal Ontogeny

GlomerularGlomerular

Filtration RateFiltration 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, 1975Aperia, 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]GuignardGuignard, J , J PediatrPediatr

87:26887:268--72, 197572, 1975

0.04 0.06 0.08 0.1 0.12

0-2 days

3-7 days

�8 days

GentamicinGentamicin

ClearanceClearance

Postnatal Postnatal AgeAge


Clearance [L/kgClearance [L/kg••hr]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, (oxidation, hydrolysis, reduction, demethylationdemethylation))

–– 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 Alcohol dehydrogenasedehydrogenase

reaches adult levels at 5 yrsreaches adult levels at 5 yrs

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

•• Phase 2Phase 2

(conjugation, (conjugation, acetylationacetylation, , methylationmethylation))

–– Conjugation:Conjugation:••

GlucuronidationGlucuronidation

↓↓

at birthat birth••

SulfatationSulfatation

↑↑

at birthat birth

–– AcetylationAcetylation

↓↓

at birth, at birth, ““fastfast””

or or ““slowslow”” phenotype by 12phenotype by 12--15 mo.15 mo.

Hepatic OntogenyHepatic Ontogeny

CytochromeCytochrome

P450 (CYP) EnzymesP450 (CYP) Enzymes

•• SuperfamilySuperfamily

of Phase 1 enzymes (oxidation, of Phase 1 enzymes (oxidation, demethylationdemethylation))

•• 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 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 OntogenyCYP2E1 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

<3

0w

<3

0w

>3

0w

>3

0w

<2

4h

<2

4h

11--

7d

7d

88--

28

d2

8d

11--

3m

o3

mo

33--

12

mo

12

mo

>1

yr

>1

yr

Ad

ul

tA

du

lt

FetusFetusPostnatal AgePostnatal Age

CYP3A7 CYP3A7 ActivityActivity

CYP3A4 CYP3A4 ActivityActivity

LaCroixLaCroix

D et al. D et al. EurEur

J J BiochemBiochem

247:625, 1997247:625, 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, 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

TheophyllineTheophylline

Urinary MetabolitesUrinary 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

PostPost--

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 H22

OO IC HIC H22

OOProteinProtein OtherOther

FatFat

0 20 40 60 80 100

Premature

Newborn

4 mo

12 mo

24 mo

36 mo

Adult

Kaufman, Pediatric Pharmacology (Kaufman, Pediatric Pharmacology (YaffeYaffe

& & ArandaAranda, , edseds) pp. 212) pp. 212--9, 19929, 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, 1994Routledge, 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 ↓ = =

α1-Acid glycoprotein ↓ =

Fetal albumin Present Absent AbsentGlobulin ↓ ↓ =

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

Plasma Protein Binding (%)Cord Adult

Acetominophen 36.8 47.5Chloramphenicol 31 42

Morphine 46 66Phenobarbital 32.4 50.7

Phenytoin 74.4 85.8Promethazine 69.8 82.7

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

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

Age [yrs]Age [yrs]

Adult Value

[%]

Adult Value

[%]

CNS VolumeCNS Volume

Body Surface AreaBody Surface Area


Adaptive IT MTX Dosing RegimenAdaptive IT MTX Dosing Regimen

AGE [YRS] MTX DOSE [MG]<1 61 82 10³ 3 12


Dose Change with Adaptive RegimenDose Change with Adaptive Regimen

0

-25

+25

+50

+75

1.5 4 7 10 13

Age [yrs]Age [yrs]

% Change in Dose

% Change in Dose

Adaptive dose12 mg/m2

dose X 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

[%]

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, 1983Bleyer, J Clin Oncol

1:317-25, 1983

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

PinkelPinkel, Cancer Res 18:853, 1958, Cancer Res 18:853, 1958

Liver Function (Children)Liver Function (Children)

MurryMurry

et al. Drug et al. Drug MetabMetab

DispDisp

23:1110, 199523:1110, 1995

400

600

800

1000

1200

1400

1600

1800

0.5 1 1.5 2

BSA [mBSA [m22]]

Liver Liver VolVol

[ml][ml]

rr22=0.75=0.750

10

20

30

40

50

0.5 1 1.5 2

AntipyrineAntipyrine

CL 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):S23McLeod et al., Br J Cancer 66 (Suppl. 18):S23--S29, 1992S29, 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

VincristineVincristine

ClearanceClearance

0 100 200 300 400 500

Infants

Children

Adolescents

0 5 10 15 20 25

Infants

Children

Adolescents


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


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

CromCrom

et al., J et al., J PediatrPediatr

125:642125:642--9, 19949, 1994

EtoposideEtoposide

ClearanceClearance

0

5

10

15

20

25

30p = 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 Oral BusulfanBusulfan

(16(16--30 mg/kg)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]

BusulfanBusulfan

CCssss

[[ngng/ml]/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, 1998Rey, Clin Pharmacokinet

35:313-29, 1998

Cystic FibrosisControls

RetinoidsRetinoids

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

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

DLTDLT PseudotumorPseudotumor cerebricerebriHA and PCHA and PC DermatologicDermatologic

99--ciscis--RARAMTDMTD 35 mg/m35 mg/m22/d/d 85 mg/m85 mg/m22/d/d 140 mg/m140 mg/m22/d/d

DLTDLT PseudotumorPseudotumor cerebricerebriHA 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 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 agemay be age--dependentdependent

CytochromeCytochrome

P450 EnzymesP450 Enzymes

PRESENT IN FETUSAPPEAR AFTER

BIRTHAPPEAR 3-4

MONTHS OF AGE

CYP3A7* CYP2D6 CYP1A2CYP1A1 CYP3A4*CYP3A5 CYP2C9

CYP2C18/19CYP2E1

* Most abundant form


in the Newbornin the Newborn

0

20

40

60

80

100

120

0 20 40 60 80 100 120


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

CreatinineCreatinine

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

15 full term15 full term23 premature23 premature

Koren

et al., Clin Pharmacol

Ther

38:680-5, 1985

Documents

Developmental Pharmacology - National Institutes of …cc.nih.gov/training/training/principles/slides/...Developmental Pharmacology Scaling adult doses to infants based on body weight