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M
)
0.001
0.01
0 6 12 18 24
0.001
0 48 96 144 192 240
Terminal t
1/2
(h) Observed Predicted
X 11 19
Y 14 64 (2.5 d)
Time (h)
3x
An Optimized Dosage Regimen for
Efficacy and Safety
1000 1000
t
i
o
n
100 mg X twice daily
40 mg Y once daily
Liver
AUC
0 14d
5x
0.1
1
10
100
0.1
1
10
100
d
i
n
e
C
o
n
c
e
n
t
r
a
t
(
M
)
Liver
AUC
0-14d
5x
NOAEL
0.001
0.01
0 2 4 6 8 10 12 14
0.001
0.01
0 2 4 6 8 10 12 14
Time (d)
F
u
r
a
m
i
d
C
eff,min
Plasma
13
Application of PBPK Modeling for the Interpretation
of Human Biomonitoring Data
Chemical concentrations Chemical concentrations
Margin of safety
Chemical concentrations
in human blood from
biomonitoring studies
Chemical concentrations
in animal blood in
toxicity studies
Pharmacokinetic
modeling
Pharmacokinetic
Modeling
F
o
r
w
a
r
d
d
o
s
i
R
e
v
e
r
s
e
d
o
s
i
Human exposures
(Chemical concentrations in
environment)
Animal exposures
(Administered doses in
toxicity studies)
Traditional risk assessment
m
e
t
r
y
m
e
t
r
y
Exposure Reconstruction Using a PBPK Model
Iraqi woman exposed during pregnancy
to grain contaminated with methylmercury
Linking Internal Dose to Health Outcome:
450 6
Maternal
E
42 g/kg/day
200
250
300
350
400
M
e
H
g
i
n
H
a
i
r
(
p
p
m
)
3
4
5
M
e
H
g
i
n
B
l
o
o
d
(
p
p
m
)
Maternal hair
Maternal blood
Infant blood
Exposure
108 days
(Clewell et al., 2000)
0
50
100
150
0 200 400 600 800
Days
M
e
0
1
2
M
e
Pregnancy
14
QSAR
In Vitro
Kinetics
Partitioning
P i l
Application of PBPK Modeling for
In Vitro to In Vivo Extrapolation
PBPK
Model
In Vitro
Dynamics
Partitioning
Metabolism
etc.
Potential
Target Tissues
Target Tissue
Responses
In Vivo
Exposure Profile
In Vivo
Human
Toxicity
Estimate
Nature of
Toxicity
In Vivo
Dose-Response
IVIVE Example:Impact of CYP2C9 Polymorphism
on Coumaden (Warfarin) Internal Dose
QC
Plasma
iv dose
QKid
Kidney
QRap
Rapidly Perfused
QSkn
Skin
(Gentry et al., 2002)
QSlw
Slowly Perfused
QLiv
Liver
VMax, KM, KMI
oral dose
15
Intrinsic
Clearance
Allele Reference Mean CV Mean CV (VmaxC/Km)
CYP2C9*1 Haining et al ., 1996
1
1.61 1.85 0.87
Km (mg/L) Vmax (mg/hr/kg
3/4
)
Metabolic Parameters for (S)-Coumaden
for Three CYP2C9 Alleles
Takahashi et al ., 1998b
2
2.13 0.0036 0.81 0.12 2.6
Sullivan-Klose et al ., 1996
2
1.01 0.046 3.57 0.078 0.28
Rettie et al ., 1994
3
3.2 1.26 2.5
Rettie et al ., 1994
4
3.2 1.05 3
CYP2C9*2 Sullivan-Klose et al ., 1996
2
1.26 0.031 3.85 0.056 0.33
Rettie et al ., 1994
3
0.21 0.52 0.4
Rettie et al ., 1994
4
0.36 0.65 0.55
Rettie et al ., 1999
5
1.1 0.036 1.85 0.17 0.59
CYP2C9*3 Haining et al ., 1996
1
0.31 9.24 0.034
Takahashi et al ., 1998b
2
0.51 0.22 3.2 0.16 0.16 ,
Sullivan-Klose et al ., 1996
2
1.37 0.044 28.4 0.059 0.048
1
baculovirus/insect cell system, purified enzyme
2
yeast expression, microsomes
3
Hep G2 cells, cell lysate
4
Hep G2 cells, particulate preparation
5
expressed in insect cells, purified enzymes
(Haber et al., 2002)
Average Prevalence of CYP2C9 Alleles
in the U.S. Population
Prevalence
S1 homozygous 78%
S1/S2 heterozygous 12%
S1/S3 heterozygous 9%
S2 homozygous 1%
(Haber et al., 2002)
S2/S3 heterozygous 1%
S3 homozygous 0.5%
16
Simulation of impact of genetic
polymorphism on Coumaden internal dose
A . C Y P 2 C 9 * 1 A l l e l e
1
2
3
4
5
a
s
m
a
C
o
n
c
e
n
tra
tio
n
(m
g
/L
)A . C Y P 2 C 9 * 1 A l l e l e
1
2
3
4
5
a
s
m
a
C
o
n
c
e
n
tra
tio
n
(m
g
/L
)
0
0 1 0 0 0 2 0 0 0 3 0 0 0 4 0 0 0 5 0 0 0 6 0 0 0
H o u r s
P
la
B . C Y P 2 C 9 * 2 A l l e l e
0
1
2
3
4
5
0 1 0 0 0 2 0 0 0 3 0 0 0 4 0 0 0 5 0 0 0 6 0 0 0
H o u r s
P
la
s
m
a
C
o
n
c
e
n
tra
tio
n
(m
g
/L
)
C . C Y P 2 C 9 *3 A lle le
5
g
/L
)
0
0 1 0 0 0 2 0 0 0 3 0 0 0 4 0 0 0 5 0 0 0 6 0 0 0
H o u r s
P
la
B . C Y P 2 C 9 * 2 A l l e l e
0
1
2
3
4
5
0 1 0 0 0 2 0 0 0 3 0 0 0 4 0 0 0 5 0 0 0 6 0 0 0
H o u r s
P
la
s
m
a
C
o
n
c
e
n
tra
tio
n
(m
g
/L
)
C . C Y P 2 C 9 *3 A lle le
5
g
/L
)
(Gentry et al., 2002)
0
1
2
3
4
0 1 0 0 0 2 0 0 0 3 0 0 0 4 0 0 0 5 0 0 0 6 0 0 0
H o u r s
P
la
s
m
a
C
o
n
c
e
n
tr
a
tio
n
(
m
g
0
1
2
3
4
0 1 0 0 0 2 0 0 0 3 0 0 0 4 0 0 0 5 0 0 0 6 0 0 0
H o u r s
P
la
s
m
a
C
o
n
c
e
n
tr
a
tio
n
(
m
g
Simulation of Impact of Genetic Polymorphism
on Warfarin Internal Exposure
200
250
A
U
C
Case 2
Case 3
Normal population
Total population
Simulation of impact of genetic
polymorphism on coumaden internal dose
50
100
150
F
r
e
q
u
e
n
c
y
o
f
(
S
)
-
W
a
r
f
a
r
i
n
A
F
r
e
q
u
e
n
c
y
0
0
5
0
1
0
0
1
5
0
2
0
0
2
5
0
3
0
0
3
5
0
4
0
0
4
5
0
5
0
0
5
5
0
6
0
0
6
5
0
7
0
0
7
5
0
8
0
0
8
5
0
9
0
0
9
5
0
1
0
0
0
(S)-Warfarin AUC
(Gentry et al., 2002)
(S)-Coumaden AUC
17
Application of PBPK Modeling to
Investigate Age-Dependent Susceptibility
An age-dependent PBPK model was developed to
simulate the physiological and biochemical changes in
humans associated with growth and aging.
All physiological and biochemical parameters in the
model change with time based on empirical data; only
the chemical specific parameters remain constant.
This model was used to simulate blood concentrations This model was used to simulate blood concentrations
of nicotine and its metabolite cotinine for a constant
daily oral dose of 1 mg/kg/day nicotine from birth to 75
years
Age-Dependent Internal Exposure to Ingested Nicotine (1 ug/kg/day)
4 . 0 E - 4 2 . 5 E - 3
N i c o ti n e
C o ti n i n e
1 . 0 E - 4
2 . 0 E - 4
3 . 0 E - 4
B
l
o
o
d
C
o
n
c
.
o
f
N
i
c
o
t
i
n
e
(
m
g
/
L
)
5 0 E 4
1 . 0 E - 3
1 . 5 E - 3
2 . 0 E - 3
B
l
o
o
d
C
o
n
c
.
o
f
C
o
t
i
n
i
n
e
(
m
g
/
L
)
0 . 0 E +0
0 2 0 4 0 6 0 8 0
A g e ( y e a r s )
0 . 0 E +0
5 . 0 E - 4
18
Clewell, H.J., Andersen, M.E., and Barton, H.A. 2002. A consistent approach for the
application of pharmacokinetic modeling in cancer and noncancer risk assessment.
Environmental Health Perspectives 110:85-93.
Clewell, H.J., Gearhart, J.M., Gentry, P.R., Covington, T.R., VanLandingham, C.B., Crump,
K.S., and Shipp, A.M. 1999. Evaluation of the uncertainty in an oral Reference Dose for
methylmercury due to interindividual variability in pharmacokinetics Risk Anal 19:547-
References
methylmercury due to interindividual variability in pharmacokinetics. Risk Anal 19:547-
558.
Clewell, H.J., Gentry, P.R., Covington, T.R., Sarangapani, R., and Teeguarden, J.G. 2004.
Evaluation of the potential impact of age- and gender-specific pharmacokinetic differences
on tissue dosimetry. Toxicol. Sci. 79:381-393.
Clewell, H.J., Gentry, P.R., Gearhart, J.M., Allen, B.C.,and Andersen, M.E. 2001.
Comparison of cancer risk estimates for vinyl chloride using animal and human data with
a PBPK model. Science of the Total Environment 274(1-3):37-66.
Clewell, H.J., Reddy, M.B., Lave, T., and Andersen, M.E. 2007. Physiologically based
pharmacokinetic modeling In: Gad SC ed Preclinical Development Handbook John pharmacokinetic modeling. In: Gad, SC, ed. Preclinical Development Handbook. John
Wiley and Sons, Hoboken, NJ.
Clewell, H. J., Tan, Y. M., Campbell, J.L., and Andersen, M.E. 2008. Quantitative
interpretation of human biomonitoring data. Tox. Appl. Pharmacol., 231:122-133.
Gentry, P.R., Hack, C.E., Haber, L., Maier, A., and Clewell, III, H.J. 2002. An Approach for
the Quantitative Consideration of Genetic Polymorphism Data in Chemical Risk
Assessment: Examples with Warfarin and Parathion. Toxicol Sci 70:120-139.
Rowland M, Balant L, and Peck C. 2004. Physiologically Based Pharmacokinetics in
Drug Development and Regulatory Science: A Workshop Report, AAPS PharmSci. 6(1):E6.