Newborns, Older Children, and Adults-Comparisons of Pharmacokinetics and
Pharmacokinetic Variability
Dale Hattis, Abel Russ, Gary Ginsberg, Prerna Banati,
Mary Kozlak, and Rob Goble
EPA/State of Connecticut Cooperative Agreement,
Dr. Bob Sonawane, EPA Project Monitor
Outline
Objectives for Pharmacokinetic Comparisons
What Information Would We Like to Have to Improve
Risk Assessments?
What Kinds of Data are Readily Available?
How Can the Data Be Summarized and Analyzed to
Make it More Useful?
Description of the Data Collected To Date
Analysis of the Group Mean Data
Variability Among Chemicals in Group Mean
Pharmacokinetic Parameters for Young Children vs Adults
Pharmacokinetic Interindividual Variability Among Young
Children Compared with Variability Among Adults
Ideal Information for Risk Analyses
Specific to Environmental Chemicals of Concern
Representative of General Exposed Populations of
Different Ages, and Special At-Risk Subgroups
Fully Detailed Documentation with Repeated Individual
Data--Allows Separation of Real Interindividual
Variability from Measurement Errors
Treatment of Pharmacodynamic, as Well as
Pharmacokinetic Variability
Data That Are Readily Available
Pharmaceuticals, Administered to Children with
Various Medial Needs
Sometimes Individual Data, Sometimes Means and
Standard Deviations
Measurements of Pharmacokinetic Parameters Helpful
in Achieving Consistent Internal Doses With Short
Courses of Administration—Focus on Volume of
Distribution, Clearances, and Elimination Half Lives
(For Inorganics) Comparative Predictions from
Radiation Dosimetry Models
Improving the Usefulness of Available Data
with Analysis
Assemble and Consolidate Data in a Consistent Form for
Analysis
Characterize Central Tendencies by Age Group
Assess the Magnitude of Differences Among Chemicals in
Age-Specific Changes in Pharmacokinetics
Assess Whether Differences Among Chemicals in AgeSpecific Central Tendencies Are Associated with
Mechanistic Categorizations (e.g. Mode of Elimination) that
Could Be Used for Predictions for Environmental Chemicals
Assess Changes in the Form and Extent of Individual
Subject Differences by Age Group
Table 1
Section of the Summary Means Data Base
Chemical
Alfentanil
Metabolic Parameter Units
Mean
Type
CYP3A4
Cl
ml/min-kg 1.79
Std Error
N
Age Range
0.55
11
premature neonates
Mea
(
≤
Alfentanil
CYP3A4
Cl
ml/min-kg
2.78
0.45
18
full term neonates
≤
Alfentanil
Alfentanil
CYP3A4
CYP3A4
Cl
Cl
ml/min-kg
ml/min-kg
4.73
4.20
0.62
0.78
8
5
4 to 8
Adult
2
Alfentanil
CYP3A4
T1/2
min
492
72
11
premature neonates
≤
Alfentanil
CYP3A4
T1/2
min
269
32
18
full term neonates
≤
Alfentanil
Alfentanil
Alfentanil
Alfentanil
CYP3A4
CYP3A4
CYP3A4
CYP3A4
T1/2
T1/2
T1/2
T1/2
min
min
min
min
40
97
114
105
3
10
8
6
8
5
5
10
4 to 8
Adult
Adult
2
2
Combined Adult
Alfentanil
CYP3A4
Vd
ml/kg
909
135
11
premature neonates
≤
Alfentanil
CYP3A4
Vd
ml/kg
583
55
18
full term neonates
≤
Alfentanil
Alfentanil
Alfentanil
Alfentanil
CYP3A4
CYP3A4
CYP3A4
CYP3A4
Vd
Vd
Vd
Vd
ml/kg
ml/kg
ml/kg
ml/kg
164
458
294
376
39
72
17
37
8
5
5
10
4 to 8
Adult
Adult
2
2
Combined Adult
Table 2
Age Groups Represented in the Means Database
Data Groups
Premature Neonates (≤ 1 wk)
11
Full Term Neonates (≤ 1 wk)
23
Newborns 1 wk- 2 months
51
Early infants 2-6 months
23
Crawlers & Toddlers (6 months -2 yrs)
23
Pre-Adolescents (2-12 years)
55
Adolescents (12-18 years)
7
Adults
69
Total
262
Table 3
Parameters, Chemicals and Subjects in the
Means Database
Data Groups
Chemicals
Total Subjects
AUC
14
5
108
Clearance
77
22
1944
Cmax
4
2
30
T1/2
103
32
1429
Vd
64
19
803
Full database
262
35
4314
Table 4
Chemicals (Drugs) Represented
Alfentanil
Amobarbital
Ampicillin
Antipyrene
Bromsulphalein
Busulfan
Bupivacaine
Caffeine
Cimetidine
Clavulanic Acid
Fentanyl
Furosemide
Gentamicin
Ketamine
Lignocaine
Lorazepam
Mepivicaine
Metoclopramide
Midazolam
Morphine
Nifedipine
Oxazepam
Paracetamol
(acetaminophen)
Piperacillin
Quinidine
Remifentanil
Teniposide
Theophylline
Ticarcillin
Tobramycin
Tolbutamide
Triazolam
Valproic Acid
Vancomycin
Zidovudine
Predominant Modes of Elimination Represented in the
Means Database
Data
Groups
Renal
56
P450 any
134
CYP3A
52
CYP1A2
52
P450 other than 3A or 1A2
30
Glucuronidation and Sulfation
53
Unclassified
19
Table 6
Multiple Regression Analysis for the Means
Database
For Data Groups Within Each Parameter:
Log(Mean) = B1*(1
or 0 for chemical 1) + B2*(1
or 0 for chemical 2) + …
+ Ba*(1 or 0 for age group 1)
+ Bb*(1 or 0 for age group 2) + …
Chemical-specific “B’s” correct for differences among
chemicals in average clearance relative to a specific
reference chemical (e.g., theophylline)
Age-group-specific “B’s” assess the average log differences
between each age group and the reference group (adults).
Table 7
Weighting Options Explored
Equal weight for each data group
Weight Equal to the Square Root of N (some
imputations needed when N not given)
Weight Equal to the Inverse of the Square of the Ratio of the
Standard Error to the Mean (additional imputations needed
when either N or standard deviation was not given)
Table 8
Example of the Full Regression Results from One Run
Dependent Variable—Log(Mean Clearance)
Weighting—Equal Weights for Each Datagroup
RSquare
Root Mean Square Error
Mean of Response
Observations (or Sum Wgts)
Parameter Estimates
Term
Intercept
Alfentanil
Antipyrene
Bromsulphalein
Bupivacaine
Caffeine
Clavulanic Acid
Fentanyl
Furosemide
Gentamicin
Ketamine
Lignocaine
Lorazepam
Midazolam
Morphine
Paracetamol (ac
Quinidine
Remifentanil
Teniposide
Ticarcillin
Valproic Acid
Vancomycin
Premature Neona
Full Term Neona
1 wk- 2 months
2-6 months
Crawlers & Todd
Pre-Adolescents
Adolescents (12
0.949
0.187
0.390
77
Estimate Std Error
-0.01
0.07
Antilog
0.26
0.41
0.55
0.95
1.45
1.28
0.77
t Ratio
-0.19
Prob>|t|
0.8497
0.73
-0.11
0.97
0.87
-0.20
0.60
1.22
0.12
0.16
1.35
1.13
-0.08
0.86
1.21
-0.41
0.82
1.65
-0.24
0.33
-0.45
0.07
0.11
0.15
0.09
0.12
0.13
0.12
0.11
0.12
0.15
0.11
0.15
0.15
0.15
0.09
0.15
0.15
0.15
0.13
0.12
0.13
0.15
6.57
-0.72
10.28
7.12
-1.6
4.86
11.29
1
1.11
12.52
7.71
-0.55
5.93
12.95
-2.73
5.33
11.35
-1.86
2.65
-3.52
0.46
<.0001
0.4732
<.0001
<.0001
0.1151
<.0001
<.0001
0.3244
0.2708
<.0001
<.0001
0.5822
<.0001
<.0001
0.0089
<.0001
<.0001
0.0697
0.0107
0.001
0.6462
-0.59
-0.39
-0.26
-0.02
0.16
0.11
-0.12
0.11
0.10
0.07
0.09
0.09
0.07
0.13
-5.17
-3.85
-3.6
-0.23
1.73
1.45
-0.9
<.0001
0.0003
0.0008
0.82
0.09
0.15
0.37
Table 9
Summary Regression Results Using Square Root of N
Weighting
Dependent Variable—Log(Mean Clearance)
Weighting—Square Root of N
RSquare
RSquare Adj
Root Mean Square Error
Mean of Response
Observations (or Sum Wgts)
Parameter
Estimates
Term
Intercept
(Chemicals omitted)
Premature Neonates
Full Term Neonates
1 wk- 2 months
2-6 months
Crawlers & Toddlers 6 mo –
2 yr
Pre-Adolescents 2-12 yr
Adolescents 12-18 yr
0.949
0.920
0.342
0.333
291
Antilog Estimate Std Error
-0.038
0.063
t Ratio Prob>|t|
-0.6
0.5536
0.25
0.43
0.59
0.97
1.49
-0.611
-0.371
-0.233
-0.011
0.174
0.108
0.093
0.068
0.095
0.091
-5.64
-3.99
-3.41
-0.12
1.92
<.0001
0.0002
0.0013
0.91
0.06
1.35
0.84
0.131
-0.075
0.070
0.120
1.86
-0.62
0.07
0.54
Table 10
Summary Regression Results Using Inverse Standard Error
Variance Weighting
Dependent Variable—Log(Mean Clearance)
Weighting—Inverse Standard Error Variance
RSquare
RSquare Adj
Root Mean Square Error
Mean of Response
Observations (or Sum Wgts)
0.983
0.973
1.455
0.467
27236
Parameter
Estimates
Term
Antilog Estimate Std Error
Intercept
-0.045
0.036
(Chemicals omitted)
Premature Neonates
0.29
-0.530
0.120
Full Term Neonates
0.62
-0.211
0.046
1 wk- 2 months
0.73
-0.136
0.043
2-6 months
1.14
0.056
0.061
Crawlers & Toddlers 6 mo – 1.55
0.190
0.065
2 yr
Pre-Adolescents 2-12 yr
1.33
0.125
0.042
Adolescents 12-18 yr
0.88
-0.055
0.096
t Ratio Prob>|t|
-1.23
0.22
-4.43
-4.53
-3.17
0.92
2.9
<.0001
<.0001
0.0027
0.36
0.0056
3.02
-0.57
0.0041
0.57
Table 11
Summary Regression Results Using Inverse Standard Error
Variance Weighting
Dependent Variable—Log(Elimination Half Life)
Weighting— Inverse Standard Error Variance
RSquare
RSquare Adj
Root Mean Square Error
Mean of Response
Observations (or Sum Wgts)
0.984
0.975
2.514
-0.172
39462
Parameter
Estimates
Term
Antilog Estimate Std Error
Intercept
0.885
0.041
(Chemicals omitted)
Premature Neonates
3.91
0.592
0.141
Full Term Neonates
2.05
0.313
0.072
1 wk- 2 months
1.88
0.275
0.051
2-6 months
1.17
0.067
0.066
Crawlers & Toddlers 6 mo – 0.86
-0.065
0.088
2 yr
Pre-Adolescents 2-12 yr
0.98
-0.008
0.046
Adolescents 12-18 yr
1.06
0.027
0.169
t Ratio Prob>|t|
21.84 <.0001
4.19
4.36
5.38
1.02
-0.74
<.0001
<.0001
<.0001
0.31
0.46
-0.18
0.16
0.86
0.87
Table 12
Summary Regression Results Using Inverse Standard Error
Variance Weighting
Dependent Variable—Log(Volume of Distribution)
Weighting— Inverse Standard Error Variance
RSquare
RSquare Adj
Root Mean Square Error
Mean of Response
Observations (or Sum Wgts)
0.933
0.889
1.780
-0.256
15421
Parameter
Estimates
Term
Antilog Estimate Std Error
Intercept
-0.378
0.033
(Chemicals omitted)
Premature Neonates
1.84
0.265
0.115
Full Term Neonates
1.09
0.038
0.111
1 wk- 2 months
1.46
0.166
0.073
2-6 months
1.27
0.102
0.089
Crawlers & Toddlers 6 mo – 1.38
0.138
0.088
2 yr
Pre-Adolescents 2-12 yr
1.07
0.029
0.044
Adolescents 12-18 yr
0.94
-0.027
0.187
t Ratio Prob>|t|
-11.52 <.0001
2.29
0.34
2.28
1.15
1.58
0.0276
0.74
0.02
0.26
0.12
0.65
-0.14
0.52
0.89
Table 13
Summary Regression Results for Elimination Half Lives for Chemical
Subsets by Mode of Elimination
Any P450:
Term
Antilog Estimate Std Error t Ratio Prob>|t|
Premature Neona
4.40
0.644
0.211
3.04
0.0051
Full Term Neona
2.27
0.356
0.110
3.22
0.0033
1 wk- 2 months
2.12
0.326
0.076
4.26
0.0002
2-6 months
1.35
0.129
0.099
1.31
0.20
Crawlers & Todd
0.59
-0.232
0.182
-1.28
0.21
Pre-Adolescents
1.19
0.074
0.079
0.94
0.36
Adolescents (12
1.41
0.148
0.682
0.22
0.83
Glucuronidation and/or Sulfation:
Term
Antilog Estimate Std Error
Premature Neona
3.50
0.544
0.119
Full Term Neona
2.19
0.341
0.074
1 wk- 2 months
1.71
0.234
0.218
2-6 months
0.79
-0.104
0.148
Crawlers & Todd
1.35
0.130
0.195
Pre-Adolescents
1.55
0.190
0.100
Adolescents (12
1.66
0.221
0.137
Renal Elimination:
Term
Premature Neona
Full Term Neona
1 wk- 2 months
2-6 months
Crawlers & Todd
Pre-Adolescents
Adolescents (12
Antilog Estimate Std Error
No data
2.79
0.446
0.291
2.76
0.441
0.177
1.19
0.075
0.133
0.86
-0.064
0.129
0.67
-0.172
0.084
No data
Figure 1
t Ratio
4.58
4.61
1.07
-0.71
0.67
1.89
1.62
Prob>|t|
0.0026
0.0025
0.32
0.50
0.53
0.10
0.15
t Ratio
Prob>|t|
1.54
2.49
0.56
-0.5
-2.04
0.14
0.025
0.58
0.62
0.059
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