Transcript Pediatric Pharmacology

Developmental Pharmacology
Scaling adult doses to infants based on body
weight or surface area does not account for
developmental changes that affect drug
disposition or tissue/organ sensitivity.
Chloramphenicol
H
Cl
OH
N
O2N
Cl
H O
OH
 Natural product of Streptomyces (1947)
 Inhibits protein synthesis (bacteriostatic)
 Eliminated by glucuronide conjugation (90%) and
renal excretion (<10%)
 Nursery infections treated with high doses
Chloramphenicol in Infants
 3320 gm infant, 44 week gestation
 Meconium stained, foul smelling, timing of ROM
unknown
 Procaine penicillin (50,00 units) + chloramphenicol
(250 mg) IM q8h - 230 mg/kg/day x 72 hr
 Day 4, gray color & cold, moist skin
 Died at 106 hr, 8 hr after onset of vascular collapse
Sutherland, Am J Dis Child 97:761-7, 1959
Chloramphenicol in Premature Infants
Premature infants born ≥24 hrs after ROM
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, 1959
Gray Baby Syndrome
No Antibiotics
Pen + Strep
Chloramphenicol
Jaundice
Vomiting
4
Anorexia
4.1
Resp. distress
4.3
Abd. distention
4.5
Cyanosis
4.6
Green stools
4.7
Lethargy
5
Ashen color
5.3
Death
5.7
0
Burns et al., NEJM 261:1318-21, 1959
10
20
30
40
50
% of Infants
60
70
80
Chloramphenicol Blood Levels
Chloramphenicol doses
200
150
Total Nitro
Compounds 100
[µg/ml]
50
Therapeutic range
0
0
1
2
Day of Life
Burns et al., NEJM 261:1318-21, 1959
3
4
Chloramphenicol Pharmacokinetics
50
30
Total Nitro
Compounds
[µg/ml]
10
8
10-16 days (n=3)
t1/2 - 10 hrs
1-2 days (n=5)
t1/2 - 26 hrs
6
4-5 yrs. (n=3)
t1/2 - 4 hrs
4
0
12
24
36
Time [hr]
Weiss et al., NEJM 262:787-94, 1960
48
60
Repeated Administration
30
25
20
Total Nitro
Compounds 15
[µg/ml]
10
5
0
0
5
10
15
20
Day of Life
Weiss et al., NEJM 262:787-94, 1960
25
30
Drug Use in Infants and Children
 Scaling adult doses based on body weight or
surface area does not account for developmental
changes that affect drug disposition or
tissue/organ sensitivity.
 Pharmacologic impact of developmental changes
are often discovered when unexpected or severe
toxicity in infants and children leads to detailed
pharmacologic studies.
 Therapeutic tragedies could be avoided by
performing pediatric pharmacologic studies
during the drug development process (before
wide-spread use of agents in infants and
children).
Zidovudine
O
CH 3
HN
O
HOCH 2
 Synthetic nucleoside analog
N
O
N3
 Inhibits HIV reverse transcriptase
 Eliminated by glucuronide conjugation (67%) and
renal excretion (33%)
 Perinatal therapy to prevent HIV transmission
Zidovudine in the Newborn
7
6
5
ZDV AUC
[µg•hr/ml]
4
3
2
1
0
0.1
1
Age [weeks]
Boucher et al., J Pediatr 122:137-44, 1993
10
Zidovudine in Newborns
Group
Age
(days)
Clearance
(ml/min/kg)
t1/2
(hr)
Preterm
5.5
17.7
2.5
4.4
7.2
4.4
Term
² 14
>14
10.9
19.0
3.1
1.9
F
(%)
89
61
Age Group
Clearance
(ml/min/kg)
t1/2
(hr)
F
(%)
1-13 yrs
Adults
24
21
1.5
1.1
68
63
Boucher et al., J Pediatr 125:642-9, 1994
Mirochnick et al., Antimicrob Agents Chemother 42:808-12, 1998
Balis et al., J Pediatr 114:880-4, 1989
Klecker et al., Clin Pharmacol Ther 41: 407-12, 1987
Prevention of HIV Transmission
Age
[weeks]
Zidovudine
Placebo
Number
HIV-infected
Rate (%)
AGE >32 WEEKS
121
127
9
31
7.4
24.4
Number
HIV-infected
Rate (%)
AGE ³ 1 YEAR
83
89
7
20
8.4
22.5
0
1
2
3
6
Zidovudine
Placebo
12
0
3
6
9
12
15
Hemoglobin [g/dl]
Connor et al., NEJM 331:1173-80, 1994
18
Ontogeny and Pharmacology
 Excretory organ (liver and kidneys) development
has the greatest impact on drug disposition
(pharmacokinetics)
 The most dramatic changes occur during the first
days to months of life
 Anticipate age-related differences in drug
disposition based on knowledge of ontogeny
 Effect of ontogeny on tissue/organ sensitivity to
drugs (pharmacodynamics) is poorly studied
 Disease states may alter a drug’s PK/PD
Renal Ontogeny
 Glomerular filtration rate
• Low at birth
• Full term newborn - 10-15 ml/min/m2
• Premature - 5-10 ml/min/m2
• GFR doubles by 1 week of age
• Adult values by 6-12 months of age
 Tubular function
• Secretory function impaired at birth
• Glomerulotubular imbalance
• Adult values by 1 year of age
Glomerular Filtration Rate
160
140
120
100
GFR
[ml/min/1.73 m2] 80
60
40
20
0
0
Aperia, Acta Pædiatr Scand 64:393-8, 1975
2
4
6
8
10
Age [months]
12
14
GFR in Infants
60
50
40
GFR
30
2
[ml/min/1.73 m ]
20
10
0
0
5
10
15
Age [days]
Guignard, J Pediatr 87:268-72, 1975
20
25
Gentamicin in the Newborn
15 full term
23 premature
120
100
80
Gentamicin
Clearance
[ml/kg•hr]
60
40
20
0
0
20
40
60
80
100
120
Creatinine Clearance [ml/kg•hr]
Koren et al., Clin Pharmacol Ther 38:680-5, 1985
Gentamicin Clearance
Premature (<37 weeks)
0-2 days
Full term
Postnatal
Age
3-7 days
8 days
•
0.04
0.06
0.08
0.1
Gentamicin Clearance [L/kg•hr]
Pons, Ther Drug Monit 10:421-7, 1988
0.12
Hepatic Ontogeny
 Phase 1 (oxidation, hydrolysis, reduction, demethylation)
• Activity low at birth
• Mature at variable rates
• Oxidative metabolism increases rapidly after birth
• Alcohol dehydrogenase reaches adult levels at 5 yrs
• Activity in young children exceeds adult levels
 Phase 2 (conjugation, acetylation, methylation)
• Conjugation:
• Glucuronidation at birth
• Sulfatation at birth
• Acetylation  at birth, “fast” or “slow” phenotype
by 12-15 mo.
Cytochrome P450 (CYP) Enzymes
 Superfamily of Phase 1 enzymes (oxidation,
demethylation)
 Nomenclature:
Family (>40%)
Subfamily (>55%)
CYP3A4
Isoform
 17 Families and 39 subfamilies in humans
 CYP1, CYP2, CYP3 are primary drug metabolizing
enzymes
 Half of all drugs metabolized by CYP3A subfamily
 CYP3A4 is most abundant hepatic P450 enzyme
and metabolizes at least 50 drugs
Cytochrome P450 Enzymes
APPEAR AF TER
APPEAR 3-4
PRESENT IN FETUS
BIRTH
MONTHS OF AG E
CYP3A7*
CYP1A1
CYP3A5
CYP2D6
CYP3A4*
CYP2C9
CYP2C18/19
CYP2E1
CYP1A2
* Most abundant form
CYP3A Ontogeny
0.15
1.5
0.1
1
CYP3A7
Activity
CYP3A4
Activity
0.05
0.5
0
0
Adult
Postnatal Age
>1yr
3-12mo
1-3mo
8-28d
1-7d
LaCroix D et al. Eur J Biochem 247:625, 1997
<24h
>30w
<30w
Fetus
Acetaminophen Metabolism
Acetaminophen
Glucuronide
Sulfate
G:S
kel
0.3
Newborn
0.15
0.75
3-9 years
0.17
1.6
12 years
0.19
1.8
Adults
0.18
0
20
40
60
% of Dose
Miller et al., Clin Pharmacol Ther 19:284-94, 1976
80
100
Theophylline Urinary Metabolites
Theophylline
Caffiene
3-MeX
1-MeUA
1,3-diMeUA
Postconception
Age
28-32 weeks
Clearance
[ml/min/kg]
20
40-50 weeks
2-3 years
Age
Range
4-9 years
100
10-16 years
70
0
20
40
60
80
% Recovered in Urine
100
Factors Affecting Drug Distribution
 Physicochemical properties of the drug
 Cardiac output/Regional blood flow
 Degree of protein/tissue binding
 Body composition
• Extracellular water
• Adipose tissue
Ontogeny of Body Composition
Protein Other
EC H2O
IC H2O
Fat
Premature
Newborn
4 mo
12 mo
24 mo
36 mo
Adult
0
20
40
60
80
% of Total Body Weight
Kaufman, Pediatric Pharmacology (Yaffe & Aranda, eds) pp. 212-9, 1992
100
Volume of Distribution of Sulfa
Newborn
Infant
Children
Adults
Elderly
0
0.1
0.2
0.3
0.4
Volume of Distribution [L/kg]
Routledge, J Antimicrob Chemother 34 Suppl A:19-24, 1994
0.5
Tissue and Organ Weight
% of Total Body Weight
Skeletal muscle
Skin
Skeleton
Heart
Liver
Kidneys
Brain
Fetus
Newborn
Adult
25
13
22
0.6
4
0.7
13
25
4
18
0.5
5
1
12
40
6
14
0.4
2
0.5
2
Plasma Proteins
Change from Adult Values
Total protein
Albumin
1-Acid glycoprotein
Fetal albumin
Globulin
Newborn



Infant


Child



Present

Absent

Absent

Protein Binding in Cord and Adult Plasma
Plasma Protein Binding (%)
Acetominophen
Chloramphenicol
Morphine
Phenobarbital
Phenytoin
Promethazine
Kurz et al., Europ J Clin Pharmacol II:463-7, 1977
Cord
Adult
36.8
31
46
32.4
74.4
69.8
47.5
42
66
50.7
85.8
82.7
30.2
17.3
CSF MTX and Age
10
Adults
Adolescents
Children
1
CSF
0.1
Methotrexate
[µM]
0.01
0.001
1
2
3
4
5
6
Time [days]
Bleyer, Cancer Treat Rep 61:1419-25, 1977
7
8
9
CNS Growth and Development
100
CNS Volume
80
Adult
Value
[%]
60
Body Surface Area
40
20
Birth
4
Bleyer, Cancer Treat Rep 61:1419-25, 1977
8
12
16
Age [yrs]
20
24
Adaptive IT MTX Dosing Regimen
AGE [YRS]
MTX DOSE [MG]
<1
1
2
³3
6
8
10
12
Bleyer, Cancer Treat Rep 61:1419-25, 1977
Dose Change with Adaptive Regimen
Adaptive dose
X 100
12 mg/m2 dose
+75
+50
%
Change +25
in Dose
0
-25
1.5
Bleyer, J Clin Oncol 1:317-25, 1983
4
7
10
Age [yrs]
13
Effect of Adaptive IT Dosing on Outcome
MTX Dose Based on BSA
20
Concurrent
10
Incidence of
CNS Relapse
[%]
0
10
0
Bleyer, J Clin Oncol 1:317-25, 1983
Isolated
MTX Dose Based on Age
<18
18- 36- 8435
83 119
Age [months]
≥12
Body Weight :Surface Area
40
Adult
1 mg/kg = 40 mg/m2
Dose = 70 mg
35
30
25
Weight
BSA
1 y.o.
1 mg/kg = 10 mg
40 mg/m2 = 18 mg
20
15
10
5
0
0
5
10
15
Age [yrs]
20
25
Anticancer Drug Clearance
DRUG
ROUTE OF CLINFANTS VS
ELIMI NATION CLCHILDREN DOSING
Methotrexate
R
 (15%)
No adjustments
Mercaptopurine
Vincristine
M
M
ND
 (/m2)
No adjustments
<1 yo, dose/kg
M
B, M
ND (/m2)
 (/m2)
M
ND
VM26/VP16
Doxorubicin
Cytarabine
McLeod et al., Br J Cancer 66 (Suppl. 18):S23-S29, 1992
No adjustments (/m2)
<2 yo, dose/kg or
Êdose/m2
No adjustment
Vincristine Clearance
Adolescents
Adolescents
Children
Children
Infants
Infants
0
100
200
300
400
Vincristine Clearance
[ml/min/m2]
Crom et al., J Pediatr 125:642-9, 1994
500
0
5
10
15
20
Vincristine Clearance
[ml/min/kg]
25
Etoposide Clearance
30
p = 0.5
25
p = 0.004
1.2
20
Etoposide
Clearance
[ml/min/m2]
0.8
15
10
0.4
5
0
<1 yr
(n=5)
>1 yr
(n=25)
<1 yr
(n=5)
>1 yr
(n=25)
0
Etoposide
Clearance
[ml/min/kg]
Doxorubicin Clearance
2500
90
p = 0.015
p = 0.39
80
2000
70
Doxorubicin
Clearance
[ml/min/m2]
60
1500
50
1000
40
30
500
20
0
<2 yr
(n=8)
>2 yr
(n=52)
<2 yr
(n=8)
>2 yr
(n=52)
10
Doxorubicin
Clearance
[ml/min/kg]
Oral Busulfan (16-30 mg/kg)
1400
Engraftment
1200
1000
Busulfan Css
[ng/ml]
800
600
400
200
Graft rejection
0
0
10
20
30
Age [yrs]
Slattery et al., Bone Marrow Transplant 16:31, 1995
40
50
60
Drug Clearance in Cystic Fibrosis
Cystic Fibrosis
Controls
Ibuprofen
Furosemide (NR)
Theophylline
Cloxacillin (NR)
Ceftazidime
Ticarcillin
Gentamycin
0
20
40
60
80
100
Clearance [ml/min•m2]
Rey, Clin Pharmacokinet 35:313-29, 1998
120
140
Retinoids
≤12 Yr.
>12 Yr
Adult
MTD
60 mg/m2/d
90 mg/m2/d
150 mg/m2/d
DLT
Pseudotumor
cerebri
HA and PC
Dermatologic
MTD
35 mg/m2/d
85 mg/m2/d
140 mg/m2/d
DLT
Pseudotumor
cerebri
HA and PC
HA, diarrhea,
dermatologic
ATRA
9-cis-RA
Conclusions
 Infants (esp. newborns) may have reduced
capacity to eliminate drugs
 Anticipate the effects of ontogeny on drug
disposition based on route of elimination
 More systematic pharmacokinetic studies
of anticancer drugs in infants are needed
 Tissue sensitivity to the toxic effects of
anticancer drugs may be age-dependent
THE END