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Figure legends
Figure 1.
Workflow for development of physiologically based pharmacokinetic
(PBPK) model in this study.
Figure 2.
Sensitivity analysis for the dose-normalized area under the concentration-time curve
from 0 to 12 h (AUC0-12h), the maximum blood concentration (Cmax), the trough blood
concentration (Cmin), and the time to maximum blood concentration (Tmax) vs. input rate
constant (kin) and output rate constant (kout) for the representative Vsac value (Vsac=1 x
10-5, 11.8, and 20.0 L/kg).
The blue and red layers represent simulated and observed values, respectively.
Figure 3. The physiologically based pharmacokinetic model-predicted vs. observed
time concentration profiles corrected for a dosage of 1 mg of tacrolimus in renal
transplant patients (n=18; a) and liver transplant patients (n=13; b). The closed circles
represent dose-normalized observed concentrations. The crosses represent dosenormalized observed concentrations in a patient which were outside the 90% prediction
40
interval using the Child-Pugh A (CP-A) Japanese population. The red, blue, and purple
lines represent the median, 5th, and 95th percentiles of predicted concentrations,
respectively. The predicted concentrations were the results of each simulation
performed using 100 subjects. The solid and broken lines represent the concentration
profile predicted by the renal transplant model using the demographics of the CP-A and
Child-Pugh B (CP-B) Japanese populations, respectively.
Figure 4. Sensitivity analysis of the dose of tacrolimus (a), hematocrit (b), albumin (c),
abundances of CYP3A4 and CYP3A5 in the liver and small intestine (d-g) for the
trough concentration (Cmin). Each red circle shows the value in a representative virtual
subject used in this simulation.
Figure 5. Simulated trough blood concentration/dose (Cmin/D) ratio of tacrolimus in
renal (a) and liver (b) transplant patients in each cytochrome P450 3A5 (CYP3A5)
phenotype, respectively. Each box plot represents an interquartile range with a 90%
prediction interval. The closed circles represent the data points outside the 5th to 95th
percentiles. Each simulation was performed using 100 subjects, a female patient
41
proportion of 50%, and an age range of 20-70 years. EM; extensive metabolizer, PM;
poor metabolizer
42
Table 1. Observed and predicted pharmacokinetic parameters of tacrolimus
Parameters
Renal transplantation
AUC0-12h/dose, ng·h/mL/mg
Cmax/dose, ng/mL/mg
Cmin/dose , ng/mL/mg
Tmax, h
Observed
(n=18)
GM
GSD
31.8
1.48
4.23
1.49
1.63
1.65
2.48
1.55
1)
Base model
(Peff=5.95×10-4)
GM
%PE
153
381
14.9
253
11.0
576
1.48
-40.5
Final model
(Peff=0.65×10-4)
GM
%PE
31.9
0.224
3.95
-6.47
1.52
-6.53
2.31
-6.77
Renal transplant
model with
CP-A Japanese
GM
%PE
Renal transplant
model with
CP-B Japanese
GM
%PE
Renal transplant
model with
CP-C Japanese
GM
%PE
GM
GSD
Renal transplant
model with
Healthy Japanese
GM
%PE
AUC0-12h/dose, ng·h/mL/mg
40.9
2.56
32.9
-19.5
38.8
-5.04
66.5
62.7
97.7
139
Cmax/dose, ng/mL/mg
4.59
2.56
4.03
-12.4
4.53
-1.56
7.05
53.2
9.83
114
Cmin/dose , ng/mL/mg
2.86
2.57
1.56
-45.1
2.00
-29.7
4.00
40.4
6.39
124
Tmax, h
2.55
1.54
2.33
-8.80
2.37
-6.89
2.48
-2.70
2.54
-0.24
Liver transplantation
Observed
(n=13)
Peff: effective permeability, GM: geometric mean, GSD: geometric standard deviation, %PE: percentage
prediction error, AUC0-12h: area under the concentration-time curve from 0 to 12 h, Cmax: maximum blood
concentration, Cmin: trough blood concentration, Tmax: time to maximum blood concentration
The predicted values were the results of each simulation performed using 100 subjects
1) Yano I et al. Eur J Clin Pharmacol. 2012;68(3):259-66.
43
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