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 Age-Specific 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
Alfentanil / CYP3A4 / Cl / ml/min-kg / 1.79 / 0.55 / 11 / premature neonates / ≤.01 / Jacqz-Aigrain and Burtin, 1996
Alfentanil / CYP3A4 / Cl / ml/min-kg / 2.78 / 0.45 / 18 / full term neonates / ≤.01 / Jacqz-Aigrain and Burtin, 1996
Alfentanil / CYP3A4 / Cl / ml/min-kg / 4.73 / 0.62 / 8 / 4 to 8 / 5.4 / Meistelman, 1987
Alfentanil / CYP3A4 / Cl / ml/min-kg / 4.20 / 0.78 / 5 / Adult / 20+ / Meistelman, 1987
Alfentanil / CYP3A4 / T1/2 / min / 492 / 72 / 11 / premature neonates / ≤.01 / Jacqz-Aigrain and Burtin, 1996
Alfentanil / CYP3A4 / T1/2 / min / 269 / 32 / 18 / full term neonates / ≤.01 / Jacqz-Aigrain and Burtin, 1996
Alfentanil / CYP3A4 / T1/2 / min / 40 / 3 / 8 / 4 to 8 / 5.4 / Meistelman, 1987
Alfentanil / CYP3A4 / T1/2 / min / 97 / 10 / 5 / Adult / 20+ / Meistelman, 1987
Alfentanil / CYP3A4 / T1/2 / min / 114 / 8 / 5 / Adult / 20+ / Lemmens, 1994
Alfentanil / CYP3A4 / T1/2 / min / 105 / 6 / 10 / Combined Adult
Alfentanil / CYP3A4 / Vd / ml/kg / 909 / 135 / 11 / premature neonates / ≤.01 / Jacqz-Aigrain and Burtin, 1996
Alfentanil / CYP3A4 / Vd / ml/kg / 583 / 55 / 18 / full term neonates / ≤.01 / Jacqz-Aigrain and Burtin, 1996
Alfentanil / CYP3A4 / Vd / ml/kg / 164 / 39 / 8 / 4 to 8 / 5.4 / Meistelman, 1987
Alfentanil / CYP3A4 / Vd / ml/kg / 458 / 72 / 5 / Adult / 20+ / Meistelman, 1987
Alfentanil / CYP3A4 / Vd / ml/kg / 294 / 17 / 5 / Adult / 20+ / Lemmens, 1994
Alfentanil / CYP3A4 / Vd / ml/kg / 376 / 37 / 10 / Combined Adult
Table 2
Age Groups Represented in the Means Database
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
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
Amobarbital / Morphine
Ampicillin / Nifedipine
Antipyrene / Oxazepam
Bromsulphalein / Paracetamol (acetaminophen)
Busulfan / Piperacillin
Bupivacaine / Quinidine
Caffeine / Remifentanil
Cimetidine / Teniposide
Clavulanic Acid / Theophylline
Fentanyl / Ticarcillin
Furosemide / Tobramycin
Gentamicin / Tolbutamide
Ketamine / Triazolam
Lignocaine / Valproic Acid
Lorazepam / Vancomycin
Mepivicaine / Zidovudine
Metoclopramide
Predominant Modes of Elimination Represented in the Means Database
Data GroupsRenal / 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 / 0.949Root Mean Square Error / 0.187
Mean of Response / 0.390
Observations (or Sum Wgts) / 77
Parameter Estimates
Term / Estimate / Std Error / t Ratio / Prob>|t|
Intercept / -0.01 / 0.07 / -0.19 / 0.8497
Alfentanil / 0.73 / 0.11 / 6.57 / <.0001
Antipyrene / -0.11 / 0.15 / -0.72 / 0.4732
Bromsulphalein / 0.97 / 0.09 / 10.28 / <.0001
Bupivacaine / 0.87 / 0.12 / 7.12 / <.0001
Caffeine / -0.20 / 0.13 / -1.6 / 0.1151
Clavulanic Acid / 0.60 / 0.12 / 4.86 / <.0001
Fentanyl / 1.22 / 0.11 / 11.29 / <.0001
Furosemide / 0.12 / 0.12 / 1 / 0.3244
Gentamicin / 0.16 / 0.15 / 1.11 / 0.2708
Ketamine / 1.35 / 0.11 / 12.52 / <.0001
Lignocaine / 1.13 / 0.15 / 7.71 / <.0001
Lorazepam / -0.08 / 0.15 / -0.55 / 0.5822
Midazolam / 0.86 / 0.15 / 5.93 / <.0001
Morphine / 1.21 / 0.09 / 12.95 / <.0001
Paracetamol (ac / -0.41 / 0.15 / -2.73 / 0.0089
Quinidine / 0.82 / 0.15 / 5.33 / <.0001
Remifentanil / 1.65 / 0.15 / 11.35 / <.0001
Teniposide / -0.24 / 0.13 / -1.86 / 0.0697
Ticarcillin / 0.33 / 0.12 / 2.65 / 0.0107
Valproic Acid / -0.45 / 0.13 / -3.52 / 0.001
Vancomycin / Antilog / 0.07 / 0.15 / 0.46 / 0.6462
Premature Neona / 0.26 / -0.59 / 0.11 / -5.17 / <.0001
Full Term Neona / 0.41 / -0.39 / 0.10 / -3.85 / 0.0003
1 wk- 2 months / 0.55 / -0.26 / 0.07 / -3.6 / 0.0008
2-6 months / 0.95 / -0.02 / 0.09 / -0.23 / 0.82
Crawlers & Todd / 1.45 / 0.16 / 0.09 / 1.73 / 0.09
Pre-Adolescents / 1.28 / 0.11 / 0.07 / 1.45 / 0.15
Adolescents (12 / 0.77 / -0.12 / 0.13 / -0.9 / 0.37
Table 9
Summary Regression Results Using Square Root of N Weighting
Dependent Variable—Log(Mean Clearance)
Weighting—Square Root of N
RSquare / 0.949RSquare Adj / 0.920
Root Mean Square Error / 0.342
Mean of Response / 0.333
Observations (or Sum Wgts) / 291
Parameter Estimates
Term / Antilog / Estimate / Std Error / t Ratio / Prob>|t|
Intercept / -0.038 / 0.063 / -0.6 / 0.5536
(Chemicals omitted)
Premature Neonates / 0.25 / -0.611 / 0.108 / -5.64 / <.0001
Full Term Neonates / 0.43 / -0.371 / 0.093 / -3.99 / 0.0002
1 wk- 2 months / 0.59 / -0.233 / 0.068 / -3.41 / 0.0013
2-6 months / 0.97 / -0.011 / 0.095 / -0.12 / 0.91
Crawlers & Toddlers 6 mo – 2 yr / 1.49 / 0.174 / 0.091 / 1.92 / 0.06
Pre-Adolescents 2-12 yr / 1.35 / 0.131 / 0.070 / 1.86 / 0.07
Adolescents 12-18 yr / 0.84 / -0.075 / 0.120 / -0.62 / 0.54
Table 10
Summary Regression Results Using Inverse Standard Error Variance Weighting
Dependent Variable—Log(Mean Clearance)
Weighting—Inverse Standard Error Variance
RSquare / 0.983RSquare Adj / 0.973
Root Mean Square Error / 1.455
Mean of Response / 0.467
Observations (or Sum Wgts) / 27236
Parameter Estimates
Term / Antilog / Estimate / Std Error / t Ratio / Prob>|t|
Intercept / -0.045 / 0.036 / -1.23 / 0.22
(Chemicals omitted)
Premature Neonates / 0.29 / -0.530 / 0.120 / -4.43 / <.0001
Full Term Neonates / 0.62 / -0.211 / 0.046 / -4.53 / <.0001
1 wk- 2 months / 0.73 / -0.136 / 0.043 / -3.17 / 0.0027
2-6 months / 1.14 / 0.056 / 0.061 / 0.92 / 0.36
Crawlers & Toddlers 6 mo – 2 yr / 1.55 / 0.190 / 0.065 / 2.9 / 0.0056
Pre-Adolescents 2-12 yr / 1.33 / 0.125 / 0.042 / 3.02 / 0.0041
Adolescents 12-18 yr / 0.88 / -0.055 / 0.096 / -0.57 / 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 / 0.984RSquare Adj / 0.975
Root Mean Square Error / 2.514
Mean of Response / -0.172
Observations (or Sum Wgts) / 39462
Parameter Estimates
Term / Antilog / Estimate / Std Error / t Ratio / Prob>|t|
Intercept / 0.885 / 0.041 / 21.84 / <.0001
(Chemicals omitted)
Premature Neonates / 3.91 / 0.592 / 0.141 / 4.19 / <.0001
Full Term Neonates / 2.05 / 0.313 / 0.072 / 4.36 / <.0001
1 wk- 2 months / 1.88 / 0.275 / 0.051 / 5.38 / <.0001
2-6 months / 1.17 / 0.067 / 0.066 / 1.02 / 0.31
Crawlers & Toddlers 6 mo – 2 yr / 0.86 / -0.065 / 0.088 / -0.74 / 0.46
Pre-Adolescents 2-12 yr / 0.98 / -0.008 / 0.046 / -0.18 / 0.86
Adolescents 12-18 yr / 1.06 / 0.027 / 0.169 / 0.16 / 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 / 0.933RSquare Adj / 0.889
Root Mean Square Error / 1.780
Mean of Response / -0.256
Observations (or Sum Wgts) / 15421
Parameter Estimates
Term / Antilog / Estimate / Std Error / t Ratio / Prob>|t|
Intercept / -0.378 / 0.033 / -11.52 / <.0001
(Chemicals omitted)
Premature Neonates / 1.84 / 0.265 / 0.115 / 2.29 / 0.0276
Full Term Neonates / 1.09 / 0.038 / 0.111 / 0.34 / 0.74
1 wk- 2 months / 1.46 / 0.166 / 0.073 / 2.28 / 0.02
2-6 months / 1.27 / 0.102 / 0.089 / 1.15 / 0.26
Crawlers & Toddlers 6 mo – 2 yr / 1.38 / 0.138 / 0.088 / 1.58 / 0.12
Pre-Adolescents 2-12 yr / 1.07 / 0.029 / 0.044 / 0.65 / 0.52
Adolescents 12-18 yr / 0.94 / -0.027 / 0.187 / -0.14 / 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 / t Ratio / Prob>|t|Premature Neona / 3.50 / 0.544 / 0.119 / 4.58 / 0.0026
Full Term Neona / 2.19 / 0.341 / 0.074 / 4.61 / 0.0025
1 wk- 2 months / 1.71 / 0.234 / 0.218 / 1.07 / 0.32
2-6 months / 0.79 / -0.104 / 0.148 / -0.71 / 0.50
Crawlers & Todd / 1.35 / 0.130 / 0.195 / 0.67 / 0.53
Pre-Adolescents / 1.55 / 0.190 / 0.100 / 1.89 / 0.10
Adolescents (12 / 1.66 / 0.221 / 0.137 / 1.62 / 0.15
Renal Elimination:
Term / Antilog / Estimate / Std Error / t Ratio / Prob>|t|Premature Neona / No data
Full Term Neona / 2.79 / 0.446 / 0.291 / 1.54 / 0.14
1 wk- 2 months / 2.76 / 0.441 / 0.177 / 2.49 / 0.025
2-6 months / 1.19 / 0.075 / 0.133 / 0.56 / 0.58
Crawlers & Todd / 0.86 / -0.064 / 0.129 / -0.5 / 0.62
Pre-Adolescents / 0.67 / -0.172 / 0.084 / -2.04 / 0.059
Adolescents (12 / No data
Figure 1
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