prediction of the effect of drug-drug interaction and pharmacogenomics ... · prediction of the...
TRANSCRIPT
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1
Prediction of the effect of drug-drug interaction and pharmacogenomics on PK/PD/TD of drugs
Yuichi SugiyamaSugiyama Laboratory, RIKEN Yokohama
JN Tata Auditorium Indian Institute of Science (IISc)Bangalore, India 560012
October 11th -13th 2018: Main Conference
Organized by:SOCIETY FOR THE STUDY OF XENOBIOTICS (SSX)-INDIA
SSX 20183rd annual conference
Dr. T. Thanga Mariappan, President- SSX, IndiaDr. Jasminder Sahi, Sanofi, China
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2
Contents
1) Introduction; Rate-determining process (focusing on the liver)
(Uptake, efflux, elimination, metabolism) DDI
2) PGx of OATP1B1: PBPK model based analysis
3) PBPK model based analysis of OATPs mediated drug-drug interaction (Top down + Bottom-up)
(i) victim drugs-perpetrator drugs
(ii)endogenous biomarker (CP-I) - rifampicin
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OATP1B1
CYP2C8CYP3A4
2C8, 3A4
2C8
N
F
CH3O
OH OHCOONa
Cerivastatin
N
F
OH
OH OHCOOH
M-1
N
F
CH3O
OH OH
COOH
OH
M-23
Uptake
Drug-interaction between Cerivastatin and Gemfibrozil/CsA
3
薬事日報平成１３年８月１５日号
薬事日報平成１３年８月２７日号
日本では、重篤な副作用のためメーカー自主回収へ
Shitara, Y. et al. J Pharmacol Exp Ther, 311(1): 228-36 (2004)
Shitara, Y. et al. J Pharmacol Exp Ther,304(2): 610-6 (2003)
Shitara, Y. and Sugiyama Y.Pharmacol Ther,112(1): 71-105 (2006)
Cyclosporine A
Gemfibrozil glucuronide
Gemfibrozil glucuronide
52 patients died (US 31). Among 31 patients,12 were given also gemfibrozil.
CerivastatinDual subsrates
Gemfibrozil-glucuronideDual inhibitors
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Substrates Uptake transporterMetabolic enzymes
Efflux transporter
Anti-Hyperlipidemic drugs (statins)
atorvastatin OATPs CYP3A4 -cerivastatin OATPs CYP2C8, 3A4 -fluvastatin OATPs CYP2C9 -pravastatin OATPs - MRP2
rosuvastatin,pitavastatin
OATPs - BCRP
Anti-hypertension or -cardiovascular disease
bosentan OATPs CYP3A4, 2C9 -torasemide OATPs CYP2C9 -telmisartan OATP1B3 UGTs -valsartan OATPs - MRP2
Anti-cancer drug
docetaxel OATP1B3 CYP3A4 -
Examples of substrates for uptake/efflux transporters and enzymes (1)
4
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Substrates Uptake transporterMetabolic enzymes
Efflux transporter
Anti-diabetes
repaglinide OATPs CYP2C8, 3A4 -nateglinide,
glibenclamideOATPs CYP2C9, 3A4
Anti-HCV
simeprevir,grazoprevir
OATP1B1 CYP3A4 -
asunaprevir,danoprevir,paritaprevir
OATPs CYP3A4 Pgp
Etc.
Montelukast OATP2B1 CYP2C8, 2C9, 3A4 -maraviroc OATP1B1 CYP3A4 Pgp
fexofenadine OATPs - Pgp5
Examples of substrates for uptake/efflux transporters and enzymes (2)
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inteff
infallint, CLPS
PSCL ×=intallint, CLCL =
inteff
intinfallint, CLPS
CLPSCL+
×=
Overall Hepatic Intrinsic Clearance (Clint,all)
1) When PSeff > CLint, (Case-2)
Degree of Sequestration (β) Uptake – limited (anionic drugs,; statins, sartans)
β =1
Degree of Active Uptake (α)
When PSinf = PSeff (passive diffusion),
α =16
Extended clearance concept
(lipophilic basic/neutral drugs; quinidine, diazepam)
Intrinsic Clearance-limited
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0
0.2
0.4
0.6
0.8
1
1 10 100
PSinf
CLmet
PSinf =100, PSeff=100, CLbile+CLmet=50(Case-2)
% of CLint,all(cont.)
(1/AUC)
PSinf↓CLmet↓
PSinf PSeff
CLbile
CLmet
metbileeff
metbileinfallint, CLCLPS
CLCLPSCL++
+×=
（sorting）（sorting）
Impact of the function of each pathway on the overall intrinsic clearance
0
0.2
0.4
0.6
0.8
1
1 10 100
PSinf
CLmet
PSinf =100, PSeff=2, CLbile+CLmet=500 (Case-1)
R value(1+I/Ki)
% CLint,all(cont.)
(1/AUC)
PSinf↓
CLmet↓
7
Graph3
1.11.1
1.21.2
1.31.3
1.41.4
1.51.5
1.61.6
1.71.7
1.81.8
1.91.9
22
33
44
55
66
77
88
99
1010
2020
3030
4040
5050
6060
7070
8080
9090
100100
PSinf
CLmet
0.9090909091
0.9375
0.8333333333
0.8823529412
0.7692307692
0.8333333333
0.7142857143
0.7894736842
0.6666666667
0.75
0.625
0.7142857143
0.5882352941
0.6818181818
0.5555555556
0.652173913
0.5263157895
0.625
0.5
0.6
0.3333333333
0.4285714286
0.25
0.3333333333
0.2
0.2727272727
0.1666666667
0.2307692308
0.1428571429
0.2
0.125
0.1764705882
0.1111111111
0.1578947368
0.1
0.1428571429
0.05
0.0731707317
0.0333333333
0.0491803279
0.025
0.037037037
0.02
0.0297029703
0.0166666667
0.0247933884
0.0142857143
0.0212765957
0.0125
0.0186335404
0.0111111111
0.0165745856
0.01
0.0149253731
Sheet1
PSinf100
PSeff100
CLbile+CLmet50
RPSinfCLmet
1.133.333333333330.3030303030.909090909131.250.9375
1.233.333333333327.77777777780.833333333329.41176470590.8823529412
1.333.333333333325.6410256410.769230769227.77777777780.8333333333
1.433.333333333323.80952380950.714285714326.31578947370.7894736842
1.533.333333333322.22222222220.6666666667250.75
1.633.333333333320.83333333330.62523.80952380950.7142857143
1.733.333333333319.60784313730.588235294122.72727272730.6818181818
1.833.333333333318.51851851850.555555555621.73913043480.652173913
1.933.333333333317.54385964910.526315789520.83333333330.625
233.333333333316.66666666670.5200.6
333.333333333311.11111111110.333333333314.28571428570.4285714286
433.33333333338.33333333330.2511.11111111110.3333333333
533.33333333336.66666666670.29.09090909090.2727272727
633.33333333335.55555555560.16666666677.69230769230.2307692308
733.33333333334.76190476190.14285714296.66666666670.2
833.33333333334.16666666670.1255.88235294120.1764705882
933.33333333333.70370370370.11111111115.26315789470.1578947368
1033.33333333333.33333333330.14.76190476190.1428571429
2033.33333333331.66666666670.052.43902439020.0731707317
3033.33333333331.11111111110.03333333331.63934426230.0491803279
4033.33333333330.83333333330.0251.23456790120.037037037
5033.33333333330.66666666670.020.99009900990.0297029703
6033.33333333330.55555555560.01666666670.8264462810.0247933884
7033.33333333330.47619047620.01428571430.70921985820.0212765957
8033.33333333330.41666666670.01250.62111801240.0186335404
9033.33333333330.37037037040.01111111110.55248618780.0165745856
10033.33333333330.33333333330.010.49751243780.0149253731
Sheet1
PSinf
CLmet
Sheet2
PSinf
CLmet
Sheet3
Graph2
1.11.1
1.21.2
1.31.3
1.41.4
1.51.5
1.61.6
1.71.7
1.81.8
1.91.9
22
33
44
55
66
77
88
99
1010
2020
3030
4040
5050
6060
7070
8080
9090
100100
PSinf
CLmet
0.9090909091
0.9996017523
0.8333333333
0.9992038217
0.7692307692
0.9988062077
0.7142857143
0.9984089101
0.6666666667
0.9980119284
0.625
0.9976152623
0.5882352941
0.9972189114
0.5555555556
0.9968228753
0.5263157895
0.9964271536
0.5
0.996031746
0.3333333333
0.9920948617
0.25
0.9881889764
0.2
0.9843137255
0.1666666667
0.98046875
0.1428571429
0.9766536965
0.125
0.9728682171
0.1111111111
0.9691119691
0.1
0.9653846154
0.05
0.9296296296
0.0333333333
0.8964285714
0.025
0.8655172414
0.02
0.8366666667
0.0166666667
0.8096774194
0.0142857143
0.784375
0.0125
0.7606060606
0.0111111111
0.7382352941
0.01
0.7171428571
Sheet1
PSinf100
PSeff2
CLbile+CLmet500
RPSinfCLmet
1.199.601593625590.54690329590.909090909199.56192751890.9996017523
1.299.601593625583.00132802120.833333333399.52229299360.9992038217
1.399.601593625576.61661048120.769230769299.48269001190.9988062077
1.499.601593625571.14399544680.714285714399.44311853620.9984089101
1.599.601593625566.4010624170.666666666799.40357852880.9980119284
1.699.601593625562.25099601590.62599.36406995230.9976152623
1.799.601593625558.58917272090.588235294199.32459276920.9972189114
1.899.601593625555.33421868080.555555555699.2851469420.9968228753
1.999.601593625552.42189138180.526315789599.24573243350.9964271536
299.601593625549.80079681270.599.20634920630.996031746
399.601593625533.20053120850.333333333398.8142292490.9920948617
499.601593625524.90039840640.2598.42519685040.9881889764
599.601593625519.92031872510.298.03921568630.9843137255
699.601593625516.60026560420.166666666797.656250.98046875
799.601593625514.22879908940.142857142997.27626459140.9766536965
899.601593625512.45019920320.12596.89922480620.9728682171
999.601593625511.06684373620.111111111196.52509652510.9691119691
1099.60159362559.96015936250.196.15384615380.9653846154
2099.60159362554.98007968130.0592.59259259260.9296296296
3099.60159362553.32005312080.033333333389.28571428570.8964285714
4099.60159362552.49003984060.02586.20689655170.8655172414
5099.60159362551.99203187250.0283.33333333330.8366666667
6099.60159362551.66002656040.016666666780.64516129030.8096774194
7099.60159362551.42287990890.014285714378.1250.784375
8099.60159362551.24501992030.012575.75757575760.7606060606
9099.60159362551.10668437360.011111111173.52941176470.7382352941
10099.60159362550.99601593630.0171.42857142860.7171428571
Sheet1
PSinf
CLmet
Sheet2
PSinf
CLmet
Sheet3
-
0 2 4 6 8 100
50
100
150
control+rifampicin+itraconazole
conc
. [pg
/ml]
atorvastatin
0 2 4 6 8 1002468
10
conc
. [pg
/ml]
*Doses of each substrates are 33µg
0 2 4 6 8 100
200
400
600
Control+rifampicin+itraconazole
conc
. [pg
/ml] pravastatin
0 2 4 6 8 100
100
200 Control+rifampicin+itraconazole
conc
entr
atio
n[p
g/m
l]
midazolam
Plasma concentrations of atorvastatin and pravastatin were greatly increased by rifampicin, but not by itraconazole
[hour]
[hour] [hour]
AUC0-10[pg*hr/ml]
ATV PRV(AUC0-8)
MDZ
Cont. 38.5±17.5
195±78.7
434±122
+RIF 439***±134
949***±179
471±168
+ITZ 36.0±19.2
386±254
755*±276
***: P
-
0 2 4 6 8 100
50
100
150
control+rifampicin+itraconazole
conc
. [pg
/ml]
atorvastatin
0 2 4 6 8 1002468
10
conc
. [pg
/ml]
[hour]Control +RIF +ITZ
AUC0-10[pg*hr/mL]
38.5±17.5
439***±134
36.0±19.2
CL of atorvastatin was inhibited only by rifampicin.→atrovastatin hepatic clearance is limited only byHepatic uptake
Effects of rifampicin and itraconazole on the PK of atorvastatin
[hour]
pg/m
L
cf. 2-hydroxyatorvastatin
9
-
10
Contents
1) Introduction; Rate-determining process (focusing on the liver)
(Uptake, efflux, elimination, metabolism) DDI
2) PGx of OATP1B1: PBPK model based analysis
3) PBPK model based analysis of OATPs mediated drug-drug interaction (Top down + Bottom-up)
(i) victim drugs-perpetrator drugs
(ii)endogenous biomarker (CP-I) - rifampicin
-
Ethnic difference in the allele frequency of mutated OATP1B1
Japanese European African American American
(n=120) (n=49)
(n=44)N130D 0.63(0.60-0.66) 0.30(0.25-0.35) 0.74(0.67-0.81)V174A 0.16(0.13-0.18) 0.14(0.10-0.18) 0.02(0-0.04)
*1*2 *2
*1 Nishizato Y et al., Clin Pharmacol Ther 73, 554-64 (2003) *2 Tirona RG et al., J Biol Chem, 276, 35669-75 (2001)
★
★
★★★★
★
★
★
★
★
★★
★★
★
★
★★
★
★
T521CVal174Ala
A388GAsn130Asp
★：reported SNPs
Allele freq.(Japanese)
OATP1B1 *1bOATP1B1 *1a
OATP1B1 *5OATP1B1 *15
130 174
N AD A
N VD V
(32.5%)(45.8%)(0.0%)
(15.0%)
Haplotype of OATP1B1(SLCO1B1)
Effect of OATP1B1*15 on the plasma conc. of pravastatin after its oral administration (10 mg)
（hr）
Pla
sma
conc. o
f pr
avas
tatin
(ng/
mL) ○: *15/*15
■: *1b/*15●: *1b/*1b
Investigation of the impact of OATP1B1 SNPs on the clinical pharmacokinetics (Uptake transporter)
Subjects with OATP1B1*15→increase in the plasma AUC of pravastatin
(Nishizato Y. et al., Clin Pharmacol Ther, 73, 554- (2003))
% o
f 1a
0
25
50
75
100
125
*1a *1b *5 *15
% o
f 1a
in vitro experiments(HEK293cells: corrected Vmax)
*150 *1a *1b *5
50
100
150
200(1) E217βG (2) Estrone-3-Sulfate
OATP1B1*15 mutant→decrease in the transport activity normalized by expression level
(Iwai M. et al., Pharmacogenetics, 14, 749-57 (2004))
11
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The impact of OATP1B1 on the PK of drugs～Plasma conc. of drugs is increased in subjects with OATP1B1*15～
HMG-CoA reductase inhibitorspravastatinsimvastatin acid (3A4)pitavastatinatorvastatin (3A4)rosuvastatin
Anti-diabetes
repaglinide (2C8, 3A4) nateglinide (2C9, 3A4)
Anti-allergic drug
fexofenadine
Anti-pulmonary hypertension drug
Atrasentan (3A4)
Anti-cancer drug
irinotecan（SN-38）
Chol-absorption inhibitor
Ezetimibe (glucuronidation)
Loop diureticsTorasemide (2C9)
12
Angiotensin receptor antagonistsOlmesartan
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Relationship between OATP1B1 genetic polymorphism andPharmacological effect and adverse effect of statins
Odds ratio of this SNPs for simvastatin-induced myopathy
521C/T vs T/T → 4.5 fold
521C/C vs T/T →16.9 fold(SEARCH Collaborative Group et al., New Engl J Med, 359, 789-99 (2008))
Simvastatin-induced myopathystrong correlation with OATP1B1 polymorphism
★Adverse EffectTarget; Muscle (via plasma)
★Pharmacological effectTarget; HMG CoA-reductase in the liver
No effect or small effect if any(Igel M et al.,Clin Pharmacol Ther, 79, 419-26 (2006))
13
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Summary-1# All of these pharmacogenetic and DDI studies on OATP1B1 suggested that the hepatic uptake plays an important role in the plasma clearance of therapeutically important drugs (mostly anionic drugs; statins, ARA, ACE inhibitors, anti-HCV drugs, anticancer drugs, etc).
14
Why did this polymorphism and/or DDI affect only side-effect (myopathy; muscle is a target tissue), and not pharmacological effect (lipid lowering effect; liver is a target organ) ?
To answer this question, it is important to estimate the exposure in the plasma (muscle ; side effect tartet) and in the liver (Pharmacological target) (statins, HCV drugs)
Watanabe T, Kusuhara H, Maeda K, Shitara Y and Sugiyama Y. Physiologically based pharmacokinetic modeling to predict transporter-mediated clearance and distribution of pravastatin in humans. J Pharmacol Exp Ther 328:652-662 (2009)
Yoshikado T, Yoshida K, Kotani N, Nakada T, Asaumi R, Toshimoto K, Maeda K, Kusuhara H, Sugiyama Y. Quantitative analyses of hepatic OATP-mediated interactions between statins and inhibitors using PBPK modeling with a parameter-optimization method. Clin Pharmacol Ther. 100:513-523(2016)
↓
-
15/24
PBPK model
PBPK modeling of pravastatin disappearance
i.v. 0.134mg/kg （observed)p.o. 0.26mg/kg （observed）
Plasma conc-time profile of pravastatin in human
Lung
Brain
Muscle
GI
QBrain
QMuscle
QLiver
PSinf
PSbile
PSeff
CLmet
Blood UrineQtotal
ka
i.v.
p.o.
Liver
inlet
Liver
Liver
Liver
Liver
inlet inlet inlet inlet
KidneyQKidney
( )
( )
( ) jH,bilemeteffhji,infbjH,jH,
jH,effhji,infji,jb,hji,
ji,
brbihb
b
CPSCLPSfCPSfdt
dCV
CPSfCPSfCCQdt
dCV
CCLCCQdt
dCV
⋅++⋅−⋅⋅=⋅
⋅⋅+⋅⋅−−=⋅
⋅−−=⋅
b
Blood
Capillary inthe liver
Hepatocytes
Extrapolated parameters based on in vitro(animal, human) and in vivo (animal)
Graph1
52018.080.36
104018.440.72
206018.81.08
409019.161.44
6012019.521.8
9018019.762.16
120202.52
18020.362.88
20.723.24
21.083.6
21.443.96
21.84.32
22.164.66
22.525
22.885.36
23.245.72
23.66.08
23.966.44
24.326.8
24.687.16
25.047.52
25.47.88
25.768.24
26.128.6
26.488.96
26.849.32
27.29.66
27.5610
27.9210.36
28.2810.72
28.6411.08
2911.44
29.3611.8
29.7212.16
30.0812.52
30.4412.88
30.813.24
31.1613.6
31.5213.96
31.8814.32
32.2414.68
32.615.04
32.9615.4
33.3215.76
33.6816.12
34.0416.48
34.416.74
34.7617
35.1217
35.4817.36
35.8417.72
36.218.08
36.5618.44
36.9218.8
37.2819.16
37.6419.52
3819.76
38.3620
38.7220.36
39.0820.72
39.4421.08
39.7221.44
4021.8
40.3622.16
40.7222.52
41.0822.88
41.4423.24
41.823.6
42.1623.96
42.5224.32
42.8824.68
43.2425.04
43.625.4
43.9625.76
44.3226.12
44.6826.48
45.0426.84
45.427.2
45.7627.56
46.1227.92
46.4828.28
46.8428.64
47.229
47.5629.36
47.9229.72
48.2830.08
48.6430.44
4930.8
49.3631.16
49.7231.52
50.0831.88
50.4432.24
50.832.6
51.1632.96
51.5233.32
51.8833.68
52.2434.04
52.634.4
52.9634.76
53.3235.12
53.6835.48
54.0435.84
54.436.2
54.7636.56
55.1236.92
55.4837.28
55.8437.64
56.238
56.5638.36
56.9238.72
57.2839.08
57.6439.44
5839.72
58.3640
58.7240.36
59.0840.72
59.4441.08
59.7241.44
6041.8
60.3642.16
60.7242.52
61.0842.88
61.4443.24
61.843.6
62.1643.96
62.5244.32
62.8844.68
63.2445.04
63.645.4
63.9645.76
64.3246.12
64.6846.48
65.0446.84
65.447.2
65.7647.56
66.1247.92
66.4848.28
66.8448.64
67.249
67.5649.36
67.9249.72
68.2850.08
68.6450.44
6950.8
69.3651.16
69.7251.52
70.0851.88
70.4452.24
70.852.6
71.1652.96
71.5253.32
71.8853.68
72.2454.04
72.654.4
72.9654.76
73.3255.12
73.6855.48
74.0455.84
74.456.2
74.7656.56
75.1256.92
75.4857.28
75.8457.64
76.258
76.5658.36
76.9258.72
77.2859.08
77.6459.44
7859.72
78.3660
78.7260.36
79.0860.72
79.4461.08
79.861.44
80.1661.8
80.5262.16
80.8862.52
81.2462.88
81.663.24
81.9663.6
82.3263.96
82.6864.32
83.0464.68
83.465.04
83.7665.4
84.1265.76
84.4866.12
84.8466.48
85.266.84
85.5667.2
85.9267.56
86.2867.92
86.6468.28
8768.64
87.3669
87.7269.36
88.0869.72
88.4470.08
88.870.44
89.1670.8
89.5271.16
89.7671.52
9071.88
90.3672.24
90.7272.6
91.0872.96
91.4473.32
91.873.68
92.1674.04
92.5274.4
92.8874.76
93.2475.12
93.675.48
93.9675.84
94.3276.2
94.6876.56
95.0476.92
95.477.28
95.7677.64
96.1278
96.4878.36
96.8478.72
97.279.08
97.5679.44
97.9279.8
98.2880.16
98.6480.52
9980.88
99.3681.24
99.7281.6
100.0881.96
100.4482.32
100.882.68
101.1683.04
101.5283.4
101.8883.76
102.2484.12
102.684.48
102.9684.84
103.3285.2
103.6885.56
104.0485.92
104.486.28
104.7686.64
105.1287
105.4887.36
105.8487.72
106.288.08
106.5688.44
106.9288.8
107.2889.16
107.6489.52
10889.76
108.3690
108.7290.36
109.0890.72
109.4491.08
109.891.44
110.1691.8
110.5292.16
110.8892.52
111.2492.88
111.693.24
111.9693.6
112.3293.96
112.6894.32
113.0494.68
113.495.04
113.7695.4
114.1295.76
114.4896.12
114.8496.48
115.296.84
115.5697.2
115.9297.56
116.2897.92
116.6498.28
11798.64
117.3699
117.7299.36
118.0899.72
118.44100.08
118.8100.44
119.16100.8
119.52101.16
119.76101.52
120101.88
120.36102.24
120.72102.6
121.08102.96
121.44103.32
121.8103.68
122.16104.04
122.52104.4
122.88104.76
123.24105.12
123.6105.48
123.96105.84
124.32106.2
124.68106.56
125.04106.92
125.4107.28
125.76107.64
126.12108
126.48108.36
126.84108.72
127.2109.08
127.56109.44
127.92109.8
128.28110.16
128.64110.52
129110.88
129.36111.24
129.72111.6
130.08111.96
130.44112.32
130.8112.68
131.16113.04
131.52113.4
131.88113.76
132.24114.12
132.6114.48
132.96114.84
133.32115.2
133.68115.56
134.04115.92
134.4116.28
134.76116.64
135.12117
135.48117.36
135.84117.72
136.2118.08
136.56118.44
136.92118.8
137.28119.16
137.64119.52
138119.76
138.36120
138.72120.36
139.08120.72
139.44121.08
139.8121.44
140.16121.8
140.52122.16
140.88122.52
141.24122.88
141.6123.24
141.96123.6
142.32123.96
142.68124.32
143.04124.68
143.4125.04
143.76125.4
144.12125.76
144.48126.12
144.84126.48
145.2126.84
145.56127.2
145.92127.56
146.28127.92
146.64128.28
147128.64
147.36129
147.72129.36
148.08129.72
148.44130.08
148.8130.44
149.16130.8
149.52131.16
149.88131.52
150.24131.88
150.6132.24
150.96132.6
151.32132.96
151.68133.32
152.04133.68
152.4134.04
152.76134.4
153.12134.76
153.48135.12
153.84135.48
154.2135.84
154.56136.2
154.92136.56
155.28136.92
155.64137.28
156137.64
156.36138
156.72138.36
157.08138.72
157.44139.08
157.8139.44
158.16139.8
158.52140.16
158.88140.52
159.24140.88
159.6141.24
159.96141.6
160.32141.96
160.68142.32
161.04142.68
161.4143.04
161.76143.4
162.12143.76
162.48144.12
162.84144.48
163.2144.84
163.56145.2
163.92145.56
164.28145.92
164.64146.28
165146.64
165.36147
165.72147.36
166.08147.72
166.44148.08
166.8148.44
167.16148.8
167.52149.16
167.88149.52
168.24149.88
168.6150.24
168.96150.6
169.32150.96
169.68151.32
170.04151.68
170.4152.04
170.76152.4
171.12152.76
171.48153.12
171.84153.48
172.2153.84
172.56154.2
172.92154.56
173.28154.92
173.64155.28
174155.64
174.36156
174.72156.36
175.08156.72
175.44157.08
175.8157.44
176.16157.8
176.52158.16
176.88158.52
177.24158.88
177.6159.24
177.96159.6
178.32159.96
178.68160.32
179.04160.68
179.4161.04
179.7161.4
180161.76
180162.12
162.48
162.84
163.2
163.56
163.92
164.28
164.64
165
165.36
165.72
166.08
166.44
166.8
167.16
167.52
167.88
168.24
168.6
168.96
169.32
169.68
170.04
170.4
170.76
171.12
171.48
171.84
172.2
172.56
172.92
173.28
173.64
174
174.36
174.72
175.08
175.44
175.8
176.16
176.52
176.88
177.24
177.6
177.96
178.32
178.68
179.04
179.4
179.7
180
180
iv
po
Time (min)
Plasma concentration(μM)
0.9406494961
0.0111982083
0.00316269
1.298
0.4591265398
0.0447928331
0.00476181
1.252
0.2575587906
0.0515117581
0.00633922
1.21
0.1119820829
0.0403135498
0.00789059
1.171
0.0671892497
0.0302351624
0.00941402
1.134
0.0358342665
0.0201567749
0.0104134
1.098
0.0223964166
0.0113995
1.064
0.0100783875
0.0128528
1.032
0.0142748
1.001
0.0156647
0.971
0.0170224
0.943
0.0183476
0.916
0.0196403
0.891
0.0209006
0.868
0.0221286
0.844
0.0233247
0.821
0.0244892
0.799
0.0256224
0.778
0.026725
0.758
0.0277972
0.738
0.0288398
0.72
0.0298533
0.701
0.0308382
0.684
0.0317952
0.667
0.0327248
0.651
0.0336277
0.636
0.0345045
0.622
0.0353558
0.608
0.0361822
0.594
0.0369844
0.58
0.037763
0.567
0.0385185
0.555
0.0392515
0.542
0.0399627
0.53
0.0406525
0.519
0.0413216
0.508
0.0419704
0.497
0.0425996
0.486
0.0432096
0.476
0.043801
0.466
0.0443742
0.457
0.0449296
0.448
0.0454679
0.439
0.0459894
0.43
0.0464946
0.421
0.0469838
0.413
0.0474576
0.407
0.0479163
0.401
0.0483603
0.401
0.0487899
0.393
0.0492056
0.386
0.0496078
0.379
0.0499967
0.371
0.0503727
0.364
0.0507361
0.357
0.0510872
0.351
0.0514264
0.346
0.0517539
0.342
0.0520701
0.336
0.0523752
0.33
0.0526695
0.324
0.052891
0.318
0.0531064
0.312
0.0533742
0.307
0.0536321
0.301
0.0538803
0.296
0.0541192
0.291
0.0543488
0.285
0.0545694
0.28
0.0547812
0.276
0.0549845
0.271
0.0551794
0.266
0.0553661
0.261
0.0555448
0.257
0.0557158
0.253
0.0558791
0.248
0.056035
0.244
0.0561836
0.24
0.0563251
0.236
0.0564597
0.232
0.0565874
0.228
0.0567086
0.224
0.0568233
0.221
0.0569316
0.217
0.0570338
0.213
0.0571299
0.21
0.0572201
0.206
0.0573046
0.203
0.0573833
0.2
0.0574566
0.196
0.0575245
0.193
0.057587
0.19
0.0576445
0.187
0.0576968
0.184
0.0577443
0.181
0.0577869
0.178
0.0578248
0.175
0.0578581
0.173
0.0578869
0.17
0.0579113
0.167
0.0579314
0.165
0.0579473
0.162
0.057959
0.16
0.0579668
0.157
0.0579706
0.155
0.0579705
0.152
0.0579667
0.15
0.0579592
0.148
0.0579481
0.145
0.0579335
0.143
0.0579155
0.141
0.0578941
0.139
0.0578694
0.137
0.0578415
0.135
0.0578105
0.133
0.0577764
0.131
0.0577394
0.129
0.0577085
0.127
0.0576759
0.126
0.0576315
0.124
0.0575843
0.122
0.0575344
0.12
0.0574819
0.118
0.0574269
0.116
0.0573693
0.115
0.0573093
0.113
0.0572469
0.111
0.0571821
0.11
0.057115
0.108
0.0570458
0.107
0.0569743
0.105
0.0569007
0.104
0.0568251
0.102
0.0567474
0.101
0.0566678
0.099103
0.0565862
0.0976855
0.0565028
0.096292
0.0564175
0.0949223
0.0563304
0.0935764
0.0562416
0.092253
0.0561511
0.0909529
0.0560589
0.0896744
0.0559651
0.0884182
0.0558697
0.087183
0.0557728
0.0859689
0.0556744
0.0847755
0.0555746
0.0836023
0.0554733
0.0824488
0.0553706
0.0813149
0.0552666
0.0802001
0.0551613
0.0791043
0.0550547
0.0780267
0.0549468
0.0769675
0.0548378
0.0759257
0.0547276
0.074902
0.0546162
0.073895
0.0545037
0.072905
0.0543902
0.0719316
0.0542755
0.0709741
0.0541599
0.0700332
0.0540433
0.0691074
0.0539257
0.0681976
0.0538072
0.0673025
0.0536878
0.0664224
0.0535675
0.0655567
0.0534463
0.0647056
0.0533244
0.0638684
0.0532016
0.0630452
0.053078
0.0624143
0.0529537
0.0617913
0.0528287
0.0610024
0.052703
0.0602262
0.0525765
0.059463
0.0524495
0.0587119
0.0523218
0.0579737
0.0521934
0.0572472
0.0520645
0.0565325
0.051935
0.0558298
0.051805
0.055138
0.0516744
0.0544581
0.0515433
0.053789
0.0514118
0.0531308
0.0512797
0.0524832
0.0511472
0.0518461
0.0510142
0.0512192
0.0508809
0.0506024
0.0507471
0.0499957
0.050613
0.0493984
0.0504785
0.0488114
0.0503436
0.0482331
0.0502084
0.0476647
0.0500729
0.0471049
0.0499371
0.0465544
0.049801
0.0460123
0.0496646
0.0454792
0.0495279
0.0449542
0.049391
0.044438
0.0492539
0.0439296
0.0491166
0.0434295
0.048979
0.0429372
0.0488413
0.0424523
0.0487494
0.0419757
0.0486574
0.0415061
0.0485193
0.0410442
0.048381
0.0405892
0.0482426
0.0401417
0.048104
0.0397009
0.0479654
0.0392671
0.0478267
0.0388401
0.0476878
0.0384194
0.0475489
0.0380057
0.0474099
0.0375979
0.0472708
0.037197
0.0471318
0.0368017
0.0469926
0.0364129
0.0468534
0.0360299
0.0467142
0.0356527
0.046575
0.0352815
0.0464358
0.0349155
0.0462966
0.0345557
0.0461575
0.0342008
0.0460183
0.0338518
0.0458792
0.0335078
0.0457401
0.033169
0.045601
0.0328354
0.0454621
0.0325065
0.0453232
0.0321831
0.0451843
0.031864
0.0450455
0.0315502
0.0449069
0.0312407
0.0447683
0.0309359
0.0446298
0.0306358
0.0444914
0.0303397
0.0443532
0.0300485
0.044215
0.0297611
0.044077
0.0294785
0.0439391
0.0291995
0.0438014
0.0289251
0.0436638
0.0286543
0.0435263
0.0283875
0.043389
0.0281248
0.0432519
0.0278653
0.0431149
0.0276105
0.0429781
0.0273589
0.0428415
0.0271109
0.0427051
0.0268664
0.0425688
0.0266254
0.0424328
0.0263881
0.0422969
0.0261535
0.0421612
0.0259232
0.0420258
0.0256955
0.0418905
0.0254714
0.0417555
0.0253236
0.0416206
0.0251773
0.041486
0.0249602
0.0413517
0.0247463
0.0412175
0.0245352
0.0410836
0.0243273
0.0409499
0.0241221
0.0408165
0.0239195
0.0406833
0.0237202
0.0405503
0.0235233
0.0404176
0.0233292
0.0402852
0.0231378
0.0401529
0.0229487
0.040021
0.0227627
0.0398893
0.0225786
0.0397579
0.0223977
0.0396268
0.0222187
0.0394959
0.0220423
0.0393653
0.0218683
0.039235
0.0216965
0.0391049
0.0215269
0.0389751
0.0213596
0.0388456
0.0211946
0.0387164
0.0210314
0.0385875
0.020871
0.0384589
0.0207121
0.0383305
0.0205558
0.0382025
0.0204011
0.0380747
0.0202486
0.0379473
0.0200978
0.0378201
0.0199493
0.0376932
0.0198025
0.0375667
0.0196576
0.0374825
0.0195146
0.0373984
0.0193731
0.0372726
0.0192338
0.037147
0.0190959
0.0370218
0.01896
0.0368968
0.0188256
0.0367722
0.018693
0.0366479
0.0185617
0.0365239
0.0184326
0.0364003
0.0183046
0.0362769
0.0181784
0.0361539
0.0180537
0.0360311
0.0179303
0.0359087
0.0178087
0.0357867
0.0176882
0.0356649
0.0175695
0.0355434
0.0174519
0.0354223
0.017336
0.0353015
0.017221
0.0351811
0.017108
0.0350609
0.0169959
0.0349411
0.0168851
0.0348216
0.0167758
0.0347024
0.0166673
0.0345836
0.0165608
0.0344651
0.0164547
0.0343469
0.0163506
0.0342291
0.0162471
0.0341116
0.0161452
0.0339944
0.0160441
0.0338775
0.0159441
0.033761
0.0158455
0.0336448
0.0157474
0.0335289
0.0156513
0.0334134
0.0155558
0.0332982
0.0154612
0.0331834
0.0153679
0.0330688
0.0152754
0.0329546
0.015184
0.0328408
0.0150936
0.0327272
0.0150041
0.032614
0.0149155
0.0325012
0.0148279
0.0323887
0.0147413
0.0322765
0.0146555
0.0321646
0.0145706
0.0320531
0.0144866
0.0319419
0.0144035
0.031831
0.0143213
0.0317205
0.0142398
0.0316103
0.0141592
0.0315005
0.0141058
0.0313909
0.0140531
0.0312818
0.0139743
0.0311729
0.0138964
0.0310644
0.0138192
0.0309562
0.0137429
0.0308484
0.0136672
0.0307408
0.0135924
0.0306336
0.0135181
0.0305268
0.0134447
0.0304203
0.013372
0.0303141
0.0132998
0.0302082
0.0132286
0.0301027
0.0131578
0.0299975
0.0130879
0.0298926
0.0130183
0.0297881
0.0129499
0.0296838
0.0128817
0.02958
0.0128144
0.0294764
0.0127476
0.0293732
0.0126812
0.0292703
0.0126158
0.0291677
0.0125507
0.0290655
0.0124862
0.0289636
0.0124225
0.028862
0.0123589
0.0287607
0.0122965
0.0286598
0.0122341
0.0285592
0.0121728
0.0284589
0.0121115
0.0283589
0.0120512
0.0282593
0.011991
0.02816
0.0119316
0.0280609
0.0118724
0.0279623
0.0118141
0.0278639
0.0117561
0.0277659
0.0116986
0.0276682
0.0116416
0.0275708
0.0115847
0.0274737
0.0115289
0.0273769
0.0114731
0.0272805
0.0114181
0.0271844
0.0113633
0.0270886
0.011309
0.0269931
0.0112552
0.0268979
0.0112015
0.026803
0.0111488
0.0267085
0.011096
0.0266142
0.0110441
0.0265203
0.0109922
0.0264267
0.0109409
0.0263334
0.01089
0.0262404
0.0108392
0.0261477
0.0107893
0.0260554
0.0107392
0.0259633
0.0106901
0.0258715
0.0106409
0.0257801
0.0105922
0.0256889
0.010544
0.0255981
0.0104957
0.0255076
0.0104485
0.0254173
0.0104009
0.0253274
0.0103543
0.0252378
0.0103075
0.0251485
0.0102615
0.0250594
0.0102155
0.0249707
0.0101698
0.0248823
0.0101247
0.0247942
0.0100795
0.0247063
0.0100352
0.0246188
0.00999077
0.0245316
0.00994688
0.0244446
0.00990304
0.024358
0.00985979
0.0242716
0.00981655
0.0241856
0.00977388
0.0240998
0.00973117
0.0240144
0.00968915
0.0239292
0.00964712
0.0238443
0.00960527
0.0237597
0.00956408
0.0236754
0.00952282
0.0235914
0.00948214
0.0235076
0.0094413
0.0234242
0.00940125
0.023341
0.00936103
0.0232582
0.00932139
0.0231756
0.00928169
0.0230932
0.00924253
0.0230112
0.00920329
0.0229295
0.00916469
0.022848
0.00912605
0.0227668
0.00908757
0.0226859
0.00904967
0.0226053
0.00901161
0.0225249
0.00897423
0.0224449
0.00893666
0.0223651
0.0088997
0.0222856
0.00886252
0.0222063
0.00882607
0.0221273
0.0087894
0.0220486
0.00875331
0.0219702
0.00871715
0.0218921
0.00868133
0.0218142
0.00864575
0.0217365
0.00861018
0.0216592
0.00857511
0.0215821
0.00853994
0.0215053
0.00850529
0.0214288
0.00847057
0.0213525
0.00843621
0.0212765
0.00840203
0.0212007
0.00836772
0.0211252
0.00833418
0.02105
0.0083004
0.0209751
0.00826707
0.0209128
0.00823356
0.0208507
0.00820053
0.0208507
0.00816782
0.00813499
0.00810253
0.00806991
0.00803797
0.00800583
0.00797413
0.00794228
0.00791096
0.00787953
0.00784833
0.00781742
0.00778628
0.0077559
0.0077251
0.00769503
0.00766471
0.00763469
0.00760485
0.00757497
0.00754551
0.00751593
0.00748676
0.00745741
0.00742862
0.00739969
0.00737105
0.00734246
0.00731371
0.00728574
0.00725744
0.00722956
0.00720151
0.00717395
0.00714625
0.00711874
0.00709149
0.00706398
0.0070372
0.00700996
0.00698343
0.00695661
0.0069301
0.00690369
0.00687706
0.00685116
0.00682493
0.00679911
0.00677309
0.00675176
0.00673045
0.00673045
報告値
Time(hr)ivpo
9.9mg19.2mg/73.8kguM表示 ヒョウジ
0.1340.260ivpo
Dose0.1340.26mg/kg0.30011198210.5823068309umol/kg
50.4250.9406494961
100.205100.4591265398
200.1150.005200.25755879060.0111982083
400.050.02400.11198208290.0447928331
600.030.023600.06718924970.0515117581
900.0160.018900.03583426650.0403135498
1200.010.01351200.02239641660.0302351624
1800.00450.0091800.01007838750.0201567749
MOMENT parameters by PKUT Ver17
iv
i.v.
Dose0.134mg/kg
TimeConc
minμg/mL
50.42
100.205
200.115
400.05
600.03
900.016
1200.01
1800.0045
AUCMRTCLVdssVdzAUCLMRTLCLLVdssLVdzLextraAICCzket1/2
μg･min/mLminmL/min/kgL/kgL/kgμg･min/mLminmL/min/kgL/kgL/kgμg/mL1/minmin
8.177532.63527973116.38642616940.53477560187.913904318434.245305876916.93222391980.5798491873
8.515630742241.470296685515.73576920560.65256701751.18238829368.252035060743.296569244216.23841864640.70306781731.22015745552-infinite0.00450.013308461652.0831934753
8.496099724940.843321442915.77194293120.64417853491.12799595568.232504043442.653851646116.2769431140.69427431681.16411313963-19.64992392110.00445474710.01398226949.5732973258
8.451817375139.510689079715.85457825860.62642531211.02213077668.188221693541.28811055516.36496971080.67567867871.05503526664-15.18201130650.00425501940.015511301144.686591748
8.415204666638.467845385815.92355804860.6125449690.94139084598.151608985140.219528030816.43847248390.66114760480.9718322675-13.5121176630.00402075720.016914927740.9784301118
8.36068490936.995378453416.0273950590.59293954580.82754531638.097089227438.710920381316.54915689280.64063309490.85448553716-6.97290296640.00354781410.019367392635.7893906462
8.322108639836.000292154516.1016883820.57966548590.74533081718.058512958337.691496931716.62837805110.62674846030.76971074757-2.46119955690.003124040.021603411532.0850796657
8.287861617235.147868651916.16822362490.56827860030.66813522658.024265935736.818289418716.69934684040.61484138510.690083347683.88837382570.0026706440.024199028928.6435949441
extrapolation to time zero
leadAICC0t1/2ΔAUCΔAUMCΔAUCLΔAUMCLAUCMRTCLVdssVdzAUCLMRTLCLLVdssLVdzL
2-infinite0.86048780494.83201304592.151219512202.02069390081.51682488810.647319237132.591202005712.58532753790.41017095210.94566358710.272728961534.927586782613.04424564320.45560402170.9801467692
3-8.8471969580.56076035348.42458775031.401900883401.38497226510.544587436
4-7.71474484310.429815243112.2805476511.074538107801.07444363390.0406608435
5-6.18239377790.364281442615.4204893150.910703606600.9074004267-0.2404577777
6-3.44896418180.303395560419.2630809380.758488900900.742715943-0.5257113738
7-0.73562709410.260643854922.89367915230.651609637200.6200505112-0.7441344557
83.88837382570.208126240428.64359494410.520315601100.4588361696-1.040090423
MOMENT parameters by PKUT Ver17
po
p.o.
Dose0.26mg/kg
MAT128.1157718408min
TimeConcKa0.0078054402min^-1
minμg/mL
200.005
400.02
600.023
900.018
1200.0135
1800.009
AUCMRTCLVdssVdzAUCLMRTLCLLVdssLVdzLextraAICCzket1/2BACmaxTmax
μg･min/mLminmL/min/kgL/kgL/kgμg･min/mLminmL/min/kgL/kgL/kgμg/mL1/minmin%μg/mLmin
2.492589.3079237713104.31293881649.31597198822.477109000290.74929093104.96106549299.52514226870.02360
3.8243038697172.424229013567.98622935311.722473179710.06048037083.8089128699173.697470688168.260947121611.856753861810.10113261392-infinite0.0090.0067577518102.5706774811
3.6675601735160.706973846570.891815731211.39280917669.36880373863.6521691736161.985481524371.190568574211.53183853059.40828582443-18.55247750620.00889143930.007566794891.6038026339
3.6156919587157.056347745771.908780662411.29373046179.16106120873.6003009589158.337668278672.216184972111.43454234059.20022401564-23.5403598530.00881637640.007849394288.3058186946
3.9230837771178.428888545666.274394015911.825266463310.18663710763.9076927773179.693595009766.535425075711.955989727310.22675861635-15.66259244370.00930739670.0065060131106.5394696602
64.91965402314853.06217047374.004950487119.436273703419.477125017364.90426302334854.24682862674.005900196519.445628324719.481743703563.06123604310.01283647670.00020562333370.956603518
報告値
iv
po
time(min)
concentration(nmol/mL)
simulation
iv
po
time(min)
concentration(μg/mL)
Sheet3
Values at t =0.0 minutesPSinf45.5PSinf45.5PSinf55.9PSinf55.9
PSeffh2.23PSeffh2.23PSeffh9.57PSeffh9.57
CLbile9.35po 0.5823umol/kgi.v. 0.3umol/kgpo 0.5823umol/kgi.v. 0.3umol/kg
CLmet0ts1ts1ts1ts1
CLrenal11.30001.3640001.363
Cp-0.3600.361.2980.3600.361.287
Fa0.470.7200.721.2520.7200.721.225
Kpbr0.0331.0801.081.211.0801.081.171
Kplu0.671.4401.441.1711.4401.441.121
Kpmu0.21.801.81.1341.801.81.075
Kpr0.12.1602.161.0982.1602.161.033
PSeffh2.239.572.5202.521.0642.5202.520.994
PSinf45.555.92.8802.881.0322.8802.880.959
Qbr103.2403.241.0013.2403.240.926
Qh20.73.603.60.9713.603.60.896
Qmu10.73.9603.960.9433.9603.960.868
Qr15.74.3204.320.9164.3204.320.842
Qtot74.94.6604.660.8914.6804.680.817
Rb0.565050.8685.0405.040.794
Va3935.3605.360.8445.405.40.773
Vbr20.75.7205.720.8215.7605.760.753
Vh17.46.0806.080.7996.1206.120.734
Vhe6.76.4406.440.7786.4806.480.716
Vlu16.76.806.80.7586.8406.840.699
Vmu4297.1607.160.7387.207.20.683
Vr4.437.5207.520.727.5607.560.668
ex1.bolus300.17.8807.880.7017.9207.920.653
ex1.infusion08.2408.240.6848.2808.280.639
ex3.bolus08.608.60.6678.6408.640.626
ex3.infusion08.9608.960.6519090.613
fB0.8399.3209.320.6369.3609.360.601
fTh0.519.6609.660.6229.7209.720.589
flux(0,7)0100100.60810.08010.080.578
flux(0,15)010.36010.360.59410.44010.440.567
flux(0,16)010.72010.720.5810.8010.80.556
flux(0,17)011.08011.080.56711.16011.160.546
flux(0,19)011.44011.440.55511.52011.520.536
flux(1,3)011.8011.80.54211.88011.880.527
flux(2,1)11.98872812.16012.160.5312.24012.240.518
flux(3,2)012.52012.520.51912.6012.60.509
flux(3,4)012.88012.880.50812.96012.960.5
flux(3,5)013.24013.240.49713.32013.320.492
flux(3,18)013.6013.60.48613.68013.680.483
flux(4,1)7.63613213.96013.960.47614.04014.040.475
flux(5,1)8.17066214.32014.320.46614.4014.40.467
flux(6,1)15.80679414.68014.680.45714.76014.760.46
flux(6,7)015.04015.040.44815.12015.120.452
flux(6,8)015.4015.40.43915.48015.480.445
flux(7,6)015.76015.760.4315.84015.840.438
flux(8,7)016.12016.120.42116.2016.20.431
flux(8,15)016.48016.480.41316.56016.560.424
flux(8,16)0.00E+0016.74016.740.40716.78016.780.42
flux(8,17)0.00E+00170170.401170170.416
flux(8,19)0.00E+00170170.401170170.416
flux(9,8)0.00E+0017.362.58E-0417.360.39317.362.15E-0417.360.41
flux(11,6)0.00E+0017.721.57E-0317.720.38617.721.27E-0317.720.404
flux(11,15)0.00E+0018.083.16E-0318.080.37918.082.62E-0318.080.397
flux(12,1)8.63E+0018.444.76E-0318.440.37118.444.07E-0318.440.391
flux(13,11)0.00E+0018.86.34E-0318.80.36418.85.59E-0318.80.386
flux(13,16)0.00E+0019.167.89E-0319.160.35719.167.16E-0319.160.38
flux(14,13)0.00E+0019.529.41E-0319.520.35119.528.76E-0319.520.374
flux(14,17)0.00E+0019.761.04E-0219.760.34619.769.85E-0319.760.37
flux(15,11)0.00E+00201.14E-02200.342201.09E-02200.367
flux(16,13)0.00E+0020.361.29E-0220.360.33620.361.26E-0220.360.361
flux(17,14)0.00E+0020.721.43E-0220.720.3320.721.42E-0220.720.356
flux(18,14)0.00E+0021.081.57E-0221.080.32421.081.59E-0221.080.351
flux(18,19)0.00E+0021.441.70E-0221.440.31821.441.75E-0221.440.346
flux(19,18)0.00E+0021.81.83E-0221.80.31221.81.91E-0221.80.341
k(0,7)0.00E+0022.161.96E-0222.160.30722.162.07E-0222.160.336
k(0,15)0.00E+0022.522.09E-0222.520.30122.522.23E-0222.520.331
k(0,16)0.00E+0022.882.21E-0222.880.29622.882.39E-0222.880.326
k(0,17)0.00E+0023.242.33E-0223.240.29123.242.54E-0223.240.322
k(0,19)0.00E+0023.62.45E-0223.60.28523.62.69E-0223.60.317
k(1,3)6.69E+0023.962.56E-0223.960.2823.962.84E-0223.960.312
k(2,1)3.99E-0224.322.67E-0224.320.27624.322.98E-0224.320.308
k(3,2)3.54E+0124.682.78E-0224.680.27124.683.13E-0224.680.304
k(3,4)1.46E+0125.042.88E-0225.040.26625.043.26E-0225.040.299
k(3,5)1.25E-0125.42.99E-0225.40.26125.43.40E-0225.40.295
k(3,18)1.54E+0125.763.08E-0225.760.25725.763.53E-0225.760.291
k(4,1)2.54E-0226.123.18E-0226.120.25326.123.66E-0226.120.287
k(5,1)2.72E-0226.483.27E-0226.480.24826.483.79E-0226.480.283
k(6,1)5.27E-0226.843.36E-0226.840.24426.843.91E-0226.840.279
k(6,7)6.54E-0227.23.45E-0227.20.2427.24.03E-0227.20.275
k(6,8)8.50E-0327.563.54E-0227.560.23627.564.15E-0227.560.272
k(7,6)6.67E+0027.923.62E-0227.920.23227.924.26E-0227.920.268
k(8,7)2.74E-0128.283.70E-0228.280.22828.284.37E-0228.280.264
k(8,15)2.74E-0128.643.78E-0228.640.22428.644.48E-0228.640.261
k(8,16)2.74E-01293.85E-02290.221294.59E-02290.257
k(8,17)2.74E-0129.363.93E-0229.360.21729.364.69E-0229.360.254
k(8,19)2.74E-0129.724.00E-0229.720.21329.724.79E-0229.720.25
k(9,8)9.59E-0330.084.07E-0230.080.2130.084.89E-0230.080.247
k(11,6)1.54E+0130.444.13E-0230.440.20630.444.98E-0230.440.243
k(11,15)6.54E-0230.84.20E-0230.80.20330.85.07E-0230.80.24
k(12,1)2.88E-0231.164.26E-0231.160.231.165.16E-0231.160.237
k(13,11)1.54E+0131.524.32E-0231.520.19631.525.25E-0231.520.234
k(13,16)6.54E-0231.884.38E-0231.880.19331.885.34E-0231.880.231
k(14,13)1.54E+0132.244.44E-0232.240.1932.245.42E-0232.240.228
k(14,17)6.54E-0232.64.49E-0232.60.18732.65.50E-0232.60.225
k(15,11)6.67E+0032.964.55E-0232.960.18432.965.58E-0232.960.222
k(16,13)6.67E+0033.324.60E-0233.320.18133.325.66E-0233.320.219
k(17,14)6.67E+0033.684.65E-0233.680.17833.685.73E-0233.680.216
k(18,14)1.54E+0134.044.70E-0234.040.17534.045.81E-0234.040.213
k(18,19)6.54E-0234.44.75E-0234.40.17334.45.88E-0234.40.21
k(19,18)6.67E+0034.764.79E-0234.760.1734.765.95E-0234.760.208
ka8.50E-0335.124.84E-0235.120.16735.126.01E-0235.120.205
q13.00E+0235.484.88E-0235.480.16535.486.08E-0235.480.202
q20.00E+0035.844.92E-0235.840.16235.846.14E-0235.840.2
q30.00E+0036.24.96E-0236.20.1636.26.20E-0236.20.197
q40.00E+0036.565.00E-0236.560.15736.566.27E-0236.560.194
q50.00E+0036.925.04E-0236.920.15536.926.32E-0236.920.192
q60.00E+0037.285.07E-0237.280.15237.286.38E-0237.280.189
q70.00E+0037.645.11E-0237.640.1537.646.44E-0237.640.187
q80.00E+00385.14E-02380.148386.49E-02380.185
q90.00E+0038.365.18E-0238.360.14538.366.54E-0238.360.182
q110.00E+0038.725.21E-0238.720.14338.726.59E-0238.720.18
q120.00E+0039.085.24E-0239.080.14139.086.64E-0239.080.178
q130.00E+0039.445.27E-0239.440.13939.446.69E-0239.440.175
q140.00E+0039.725.29E-0239.720.13739.726.73E-0239.720.174
q150.00E+00405.31E-02400.135406.76E-02400.172
q160.00E+0040.365.34E-0240.360.13340.366.81E-0240.360.17
q170.00E+0040.725.36E-0240.720.13140.726.85E-0240.720.168
q180.00E+0041.085.39E-0241.080.12941.086.89E-0241.080.166
q190.00E+0041.445.41E-0241.440.12741.446.94E-0241.440.164
s11.36E+0041.85.43E-0241.80.12641.86.97E-0241.80.162
s1_res-42.165.46E-0242.160.12442.167.01E-0242.160.159
s1_wres-42.525.48E-0242.520.12242.527.05E-0242.520.158
s20.00E+0042.885.50E-0242.880.1242.887.09E-0242.880.156
s30.00E+0043.245.52E-0243.240.11843.247.12E-0243.240.154
s40.00E+0043.65.54E-0243.60.11643.67.16E-0243.60.152
t0.00E+0043.965.55E-0243.960.11543.967.19E-0243.960.15
44.325.57E-0244.320.11344.327.22E-0244.320.148
44.685.59E-0244.680.11144.687.25E-0244.680.146
45.045.60E-0245.040.1145.047.28E-0245.040.144
45.45.62E-0245.40.10845.47.31E-0245.40.143
45.765.63E-0245.760.10745.767.34E-0245.760.141
46.125.65E-0246.120.10546.127.36E-0246.120.139
46.485.66E-0246.481.04E-0146.487.39E-0246.480.138
46.845.67E-0246.841.02E-0146.847.41E-0246.840.136
47.25.68E-0247.21.01E-0147.27.44E-0247.20.134
47.565.69E-0247.569.91E-0247.567.46E-0247.560.133
47.925.70E-0247.929.77E-0247.927.48E-0247.920.131
48.285.71E-0248.289.63E-0248.287.51E-0248.280.129
48.645.72E-0248.649.49E-0248.647.53E-0248.640.128
495.73E-02499.36E-02497.55E-02490.126
49.365.74E-0249.369.23E-0249.367.56E-0249.360.125
49.725.75E-0249.729.10E-0249.727.58E-0249.720.123
50.085.75E-0250.088.97E-0250.087.60E-0250.080.122
50.445.76E-0250.448.84E-0250.447.62E-0250.440.121
50.85.76E-0250.88.72E-0250.87.63E-0250.81.19E-01
51.165.77E-0251.168.60E-0251.167.65E-0251.161.18E-01
51.525.77E-0251.528.48E-0251.527.66E-0251.521.16E-01
51.885.78E-0251.888.36E-0251.887.67E-0251.881.15E-01
52.245.78E-0252.248.24E-0252.247.69E-0252.241.14E-01
52.65.79E-0252.68.13E-0252.67.70E-0252.61.12E-01
52.965.79E-0252.968.02E-0252.967.71E-0252.961.11E-01
53.325.79E-0253.327.91E-0253.327.72E-0253.321.10E-01
53.685.79E-0253.687.80E-0253.687.73E-0253.681.08E-01
54.045.79E-0254.047.70E-0254.047.74E-0254.041.07E-01
54.45.80E-0254.47.59E-0254.47.75E-0254.41.06E-01
54.765.80E-0254.767.49E-0254.767.76E-0254.761.05E-01
55.125.80E-0255.127.39E-0255.127.77E-0255.121.04E-01
55.485.80E-0255.487.29E-0255.487.77E-0255.481.02E-01
55.845.80E-0255.847.19E-0255.847.78E-0255.841.01E-01
56.25.80E-0256.27.10E-0256.27.79E-0256.21.00E-01
56.565.79E-0256.567.00E-0256.567.79E-0256.569.90E-02
56.925.79E-0256.926.91E-0256.927.80E-0256.929.79E-02
57.285.79E-0257.286.82E-0257.287.80E-0257.289.68E-02
57.645.79E-0257.646.73E-0257.647.81E-0257.649.57E-02
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143.762.98E-02143.761.01E-02143.764.32E-02143.761.54E-02
144.122.97E-02144.121.01E-02144.124.30E-02144.121.54E-02
144.482.96E-02144.481.00E-02144.484.29E-02144.481.53E-02
144.842.95E-02144.849.99E-03144.844.27E-02144.841.52E-02
145.22.94E-02145.29.95E-03145.24.26E-02145.21.51E-02
145.562.93E-02145.569.90E-03145.564.24E-02145.561.51E-02
145.922.92E-02145.929.86E-03145.924.23E-02145.921.50E-02
146.282.91E-02146.289.82E-03146.284.22E-02146.281.49E-02
146.642.90E-02146.649.77E-03146.644.20E-02146.641.49E-02
1472.89E-021479.73E-031474.19E-021471.48E-02
147.362.88E-02147.369.69E-03147.364.17E-02147.361.47E-02
147.722.87E-02147.729.65E-03147.724.16E-02147.721.46E-02
148.082.86E-02148.089.61E-03148.084.14E-02148.081.46E-02
148.442.85E-02148.449.56E-03148.444.13E-02148.441.45E-02
148.82.84E-02148.89.52E-03148.84.11E-02148.81.44E-02
149.162.83E-02149.169.48E-03149.164.10E-02149.161.44E-02
149.522.82E-02149.529.44E-03149.524.08E-02149.521.43E-02
149.882.81E-02149.889.40E-03149.884.07E-02149.881.42E-02
150.242.80E-02150.249.36E-03150.244.06E-02150.241.42E-02
150.62.79E-02150.69.32E-03150.64.04E-02150.61.41E-02
150.962.78E-02150.969.28E-03150.964.03E-02150.961.40E-02
151.322.77E-02151.329.24E-03151.324.01E-02151.321.40E-02
151.682.76E-02151.689.20E-03151.684.00E-02151.681.39E-02
152.042.75E-02152.049.16E-03152.043.98E-02152.041.38E-02
152.42.74E-02152.49.13E-03152.43.97E-02152.41.38E-02
152.762.73E-02152.769.09E-03152.763.96E-02152.761.37E-02
153.122.72E-02153.129.05E-03153.123.94E-02153.121.36E-02
153.482.71E-02153.489.01E-03153.483.93E-02153.481.36E-02
153.842.70E-02153.848.97E-03153.843.91E-02153.841.35E-02
154.22.69E-02154.28.94E-03154.23.90E-02154.21.35E-02
154.562.68E-02154.568.90E-03154.563.89E-02154.561.34E-02
154.922.67E-02154.928.86E-03154.923.87E-02154.921.33E-02
155.282.66E-02155.288.83E-03155.283.86E-02155.281.33E-02
155.642.65E-02155.648.79E-03155.643.85E-02155.641.32E-02
1562.64E-021568.75E-031563.83E-021561.32E-02
156.362.63E-02156.368.72E-03156.363.82E-02156.361.31E-02
156.722.62E-02156.728.68E-03156.723.81E-02156.721.30E-02
157.082.61E-02157.088.65E-03157.083.79E-02157.081.30E-02
157.442.61E-02157.448.61E-03157.443.78E-02157.441.29E-02
157.82.60E-02157.88.58E-03157.83.76E-02157.81.29E-02
158.162.59E-02158.168.54E-03158.163.75E-02158.161.28E-02
158.522.58E-02158.528.51E-03158.523.74E-02158.521.28E-02
158.882.57E-02158.888.47E-03158.883.72E-02158.881.27E-02
159.242.56E-02159.248.44E-03159.243.71E-02159.241.26E-02
159.62.55E-02159.68.40E-03159.63.70E-02159.61.26E-02
159.962.54E-02159.968.37E-03159.963.69E-02159.961.25E-02
160.322.53E-02160.328.33E-03160.323.67E-02160.321.25E-02
160.682.52E-02160.688.30E-03160.683.66E-02160.681.24E-02
161.042.51E-02161.048.27E-03161.043.65E-02161.041.24E-02
161.42.51E-02161.48.23E-03161.43.63E-02161.41.23E-02
161.762.50E-02161.768.20E-03161.763.62E-02161.761.23E-02
162.122.49E-02162.128.17E-03162.123.61E-02162.121.22E-02
162.482.48E-02162.488.13E-03162.483.59E-02162.481.21E-02
162.842.47E-02162.848.10E-03162.843.58E-02162.841.21E-02
163.22.46E-02163.28.07E-03163.23.57E-02163.21.20E-02
163.562.45E-02163.568.04E-03163.563.56E-02163.561.20E-02
163.922.44E-02163.928.01E-03163.923.54E-02163.921.19E-02
164.282.44E-02164.287.97E-03164.283.53E-02164.281.19E-02
164.642.43E-02164.647.94E-03164.643.52E-02164.641.18E-02
1652.42E-021657.91E-031653.51E-021651.18E-02
165.362.41E-02165.367.88E-03165.363.49E-02165.361.17E-02
165.722.40E-02165.727.85E-03165.723.48E-02165.721.17E-02
166.082.39E-02166.087.82E-03166.083.47E-02166.081.16E-02
166.442.38E-02166.447.79E-03166.443.46E-02166.441.16E-02
166.82.38E-02166.87.76E-03166.83.44E-02166.81.15E-02
167.162.37E-02167.167.73E-03167.163.43E-02167.161.15E-02
167.522.36E-02167.527.70E-03167.523.42E-02167.521.14E-02
167.882.35E-02167.887.66E-03167.883.41E-02167.881.14E-02
168.242.34E-02168.247.63E-03168.243.39E-02168.241.13E-02
168.62.33E-02168.67.60E-03168.63.38E-02168.61.13E-02
168.962.33E-02168.967.57E-03168.963.37E-02168.961.12E-02
169.322.32E-02169.327.55E-03169.323.36E-02169.321.12E-02
169.682.31E-02169.687.52E-03169.683.35E-02169.681.11E-02
170.042.30E-02170.047.49E-03170.043.33E-02170.041.11E-02
170.42.29E-02170.47.46E-03170.43.32E-02170.41.11E-02
170.762.28E-02170.767.43E-03170.763.31E-02170.761.10E-02
171.122.28E-02171.127.40E-03171.123.30E-02171.121.10E-02
171.482.27E-02171.487.37E-03171.483.29E-02171.481.09E-02
171.842.26E-02171.847.34E-03171.843.27E-02171.841.09E-02
172.22.25E-02172.27.31E-03172.23.26E-02172.21.08E-02
172.562.24E-02172.567.29E-03172.563.25E-02172.561.08E-02
172.922.24E-02172.927.26E-03172.923.24E-02172.921.07E-02
173.282.23E-02173.287.23E-03173.283.23E-02173.281.07E-02
173.642.22E-02173.647.20E-03173.643.22E-02173.641.06E-02
1742.21E-021747.17E-031743.20E-021741.06E-02
174.362.20E-02174.367.15E-03174.363.19E-02174.361.06E-02
174.722.20E-02174.727.12E-03174.723.18E-02174.721.05E-02
175.082.19E-02175.087.09E-03175.083.17E-02175.081.05E-02
175.442.18E-02175.447.06E-03175.443.16E-02175.441.04E-02
175.82.17E-02175.87.04E-03175.83.15E-02175.81.04E-02
176.162.17E-02176.167.01E-03176.163.14E-02176.161.03E-02
176.522.16E-02176.526.98E-03176.523.12E-02176.521.03E-02
176.882.15E-02176.886.96E-03176.883.11E-02176.881.03E-02
177.242.14E-02177.246.93E-03177.243.10E-02177.241.02E-02
177.62.14E-02177.66.90E-03177.63.09E-02177.61.02E-02
177.962.13E-02177.966.88E-03177.963.08E-02177.961.01E-02
178.322.12E-02178.326.85E-03178.323.07E-02178.321.01E-02
178.682.11E-02178.686.82E-03178.683.06E-02178.681.00E-02
179.042.11E-02179.046.80E-03179.043.05E-02179.041.00E-02
179.42.10E-02179.46.77E-03179.43.04E-02179.49.96E-03
179.72.09E-02179.76.75E-03179.73.03E-02179.79.93E-03
1802.09E-021806.73E-031803.02E-021809.89E-03
1802.09E-021806.73E-031803.02E-021809.89E-03
Sheet3
520
1040
2060
4090
60120
90180
120
180
iv
po
Time (min)
Plasma concentration(μM)
0.9406494961
0.0111982083
0.4591265398
0.0447928331
0.2575587906
0.0515117581
0.1119820829
0.0403135498
0.0671892497
0.0302351624
0.0358342665
0.0201567749
0.0223964166
0.0100783875
-
16/24
Plasma
Liver
PSinf(OATP1B1) PSbile (MRP2/BCRP)
Effect of the transporters(influx, efflux) in the liver on the time-course and exposure of drugs in the plasma and target tissue.
Uptake transporter (OATP1B1, PSinf)
(Adverse effect)
Big effect onplasma and muscle
exposure
Small (if any) effect onLiver exposre
×1/3
×3
×3
×1/3
×1/3
×3
×1/3
×3
Efflux (biliary) transporter (MRP2, BCRP, OATP1B1, PSeff)(Pharamcological effect)
Small (if any) effect onplasma and muscle
exposure
Big effect onLiver exposre
(We need PET studies to confirm this prediction)
(20)
-
inteff
intinf
bb
CLPSCLPS
DoseAUCf
+⋅
=⋅
Vb, Cb, fb
Vi, Ci, fb
Vh, Ch, fh
QhQh
PSinf PSeff
CLint
CLr
Effect of functional alteration of metabolism/efflux process on the plasma and liver concentrations
Blood AUC
blood
liver
When PSeffCLint(intrinsic clearance-limited)
eff
intinf
bb
PSCLPS
DoseAUCf⋅
=⋅
17
In either case, the change in PSinf(uptake clearance)does not influence the liver exposure (fh ・AUCh), but influence the blood exposure
-
18
“Extended Clearance Concept”
• enough to predict the change in AUC and/or Css both in plasma and tissue
(PGx, DDI (at least for static analyses, and not for dynamic analysis)
“PBPK modeling”
• Appropriate model for describing the drug conc-time courseboth in plasma and tissue as well as AUC, Css
-
Summary :
1) Sensitivity analysis indicated that the change in hepatic uptakeability alters the plasma concentration profile sensitively (toxicity) and may not affect the profile in the liver, target tissue(pharamcological effect). GWAS for simvastatin in fact demonstrated it was the case.
2) Alteration in the biliary excretion ability (MRP2, BCRP) may affect the pharmacological effect（hepatic exposure) much more sensitively than that of the uptake, though there is little changein the plasma exposures.
⇒ We have to confirm it by PET analyses
This prediction has been supported by several studiespublished by other groups (simvastatin GWAS study,rosuvastatin Jupiter trial)
19
-
20
Contents
1) Introduction; Rate-determining process (focusing on the liver)
(Uptake, efflux, elimination, metabolism) DDI
2) PGx of OATP1B1: PBPK model based analysis
3) PBPK model based analysis of OATPs mediated drug-drug interaction (Top down + Bottom-up)
(i) victim drugs-perpetrator drugs
(ii)endogenous biomarker (CP-I) – rifampicin
-
Drug-Drug Interaction between CER and Cyclosporine A/Gemfibrozil
Plas
ma
conc
entr
atio
n of
cer
ivas
tatin
(ng/
mL)
0.01
0.1
1
10
0 4 8 12 16
healthy subjectspatients on CsA
0.1
1
10
0 6 12 18 24Time [h]
+placebo+gemfibrozil
Backman JT et al. ,Clin Pharmacol Ther., (2002)
Cmax: x 5.0
t1/2: x 1.2
Cmax: x 2.5
t1/2: x 2.4
AUC: x 3.8
AUC: x 4.4
Cyclosporine A (CsA) Gemfibrozil (GEM)
Time [h]
Mück W et al., Clin Pharmacol Ther., (1999)
(CYP3A4)CYP2C8
OATP1B1
CER
CER
M-1 M-23
M-24(minor)
CYP3A4(CYP2C8)
CYP3A4CYP2C8
CYP2C8
CsA GEM/GEM-glu
To develop PBPK models to quantitatively describe the transporter- and enzyme-mediated DDIs of CER
CLh ↓ Vd ↓ T ½ → CLh ↓ Vd T ½ 21
-
PBPK analyses of transporter/enzyme mediated complex DDI
22
Yoshikado T et al.,Clin Pharmacol Ther., (2016)
Cerivastatin (CER)
Cyclosporine A (CsA)
Gemfibrozil (GEM)
• In this analysis, CER and GEM fitting (Step3) were performed using Cluster Newton Method (CNM) and control fitting and DDI simulation (Step4) were performed using Napp (Numeric Analysis Program for Pharmacokinetics) version 2.31.
• CsA model and optimized parameters were used reported by Yoshikado et al.
-
23
Best simulation of CER vs CsA / CER vs GEM
CER vs CsA CER vs GEM
○：Observed DataBackman JT et al., Clin Pharmacol Ther. (2002)
○：Observed DataMück W et al. Clin Pharmacol Ther. (1999)
Present PBPK models were able to well reproduce the clinical DDIs
We may have to consider the inhibition of GI Pgp
Yao Y, Toshimoto K, Kim SJ, Yoshikado T, Sugiyama Y. Quantitative Analysis of Complex Drug-Drug Interactions between Cerivastatin and Metabolism/Transport Inhibitors Using Physiologically Based Pharmacokinetic Modeling. Drug Metab Dispos. 46:924-933. (2018)
-
Summary
• The concentration-time profiles for CER and GEM/GEM-glu described by PBPK models were well agreed with the clinically observed data.
• The present PBPK models were able to capture the clinical DDIs CER and CsA : using x1/2 in vivo Ki value for OATP1B1 which is
previously reported. We may have to take into account the inhibitionof intestinal Pgp to better describe this DDI
CER and GEM: using reported in vitro Ki value for OATP1B1 or CYP2C8 when fm_2C8 = 0.85 value was used
complex DDIs involving both transporters and metabolic enzymes could be quantitatively predicted by PBPK modeling approach
24
-
+ ICZ(100 mg bid for 3 days)
+ GEM(600 mg bid for 3 days)
+ ICZ and GEM
Control
Increase in repaglinide concentration by co-administration of itraconazole (ICZ) and gemfibrozil (GEM)
Diabetologia 46: 347-351 (2003)
AUC ×19.4
×8.1
×1.4
Can this drastic increase in the extent of interaction by ICZ/GEM combination be explained simply by the inhibition of enzyme/transporter?25
-
Analysis using clearance concept and PBPK modeling
50％↓
>90％↓
80％↓
OATP1B1
Uptake
Metabolism
Repaglinide
CYP2C8
CYP3A4
Liver
ICZICZ: itraconazole
GEM,GEM-glu
GEM: gemfibrozil
26
Kudo T et al., Analysis of the repaglinide concentration increase produced by gemfibrozil and itraconazole based on the inhibition of thehepatic uptake transporter and metabolic enzymes.
Drug Metab Dispos 41:362-371 (2013).
fm2C8 = 0.8
-
27
In the official labeling, the prediction of DDI using PBPK modeling has been appearing. We already have many examples.
例：iburutinib （ Bruton's tyrosine kinase （BTK）inhibitor）
-
28
Contents
1) Introduction; Rate-determining process (focusing on the liver)
(Uptake, efflux, elimination, metabolism) DDI
2) PGx of OATP1B1: PBPK model based analysis
3) PBPK model based analysis of OATPs mediated drug-drug interaction (Top down + Bottom-up)
(i) victim drugs-perpetrator drugs
(ii)endogenous biomarker (CP-I) – rifampicin
-
29
Current criteria may request pharmaceutical industry to conduct unnecessary DDI study, and overlook DDI risk.
R-value = 1 + Iu, in, max / Ki or IC50Iu, in, max = fu* Imax + (ka x Dose x Fa*Fg / Qh)
EMAR ≧ 1.04
PMDAR ≧ 1.25
FDAR ≧ 1.25
Imax/Ki ≧ 0.1
If Fa*Fg values and ka values are unknown, use 1 and 0.1 min-1If fu values are
-
Endogenous probes will offer an option in assessment of pharmacokinetic DDI during drug development
single dose
multiple dose
DDI risk using probe substrates
Phase I Phase II
Pharmacokinetic DDI risks caused by the investigational new drug can be evaluated using endogenous biomarkers during Phase I helping decision of conducting
clinical DDI study, and design of phase 3 to avoid DDI
Plasma and urine specimens are subjected to the pharmacokinetic analysis of metabolites
setting exclusion criteria of drugs to avoid DDI
-
Step 1 phase I trial of New Chemical Entity
(NCE)
CP-I levels
time
conc doses
of NCE
Obtain in vivo Ki,OATP1Bs (CP-I) using
CP-I (an endogenous probe)
Step 2
in vitro transport study to obtain inhibitory potency of NCE
using CP-I and a probe drug
PBPK modeling-based simulations
in vitro Ki,OATP1Bs (Drug) in vitro Ki,OATP1Bs (CP-I)
in vivo Ki,OATP1Bs (CP-I)
Xin vivo Ki,OATP1Bs (Drug) in vitro Ki,OATP1Bs (CP-I)
in vitro Ki,OATP1Bs (Drug) =
Step 3
Obtain
Quantitative prediction of the impact of NCE on the pharmacokinetics of a probe drug (concentration-time profiles, AUC, Cmax)
Strategy to predict DDI for a probe substrate using CP-I as an endogenous biomarker
31
Yoshikado T, Toshimoto K, Maeda K, Kusuhara H, Kimoto E, Rodrigues AD, Chiba K,Sugiyama Y. PBPK Modeling of Coproporphyrin I as an Endogenous Biomarker for Drug Interactions Involving Inhibition of Hepatic OATP1B1 and OATP1B3.CPT Pharmacometrics Syst Pharmacol. 2018 Sep 3. doi: 10.1002/psp4.12348. [Epub ahead of print]
https://www.ncbi.nlm.nih.gov/pubmed/30175555
-
32
Parameter Unit Value
CLint,all L/h/kg 39.6/42.9/47.7
vsyn nmol/h/kg
0.449/0.274/0.222
Rdif - 0.035
β - 0.8/0.5/0.2
γ - 0.020
fbile - 0.84
ktransit h-1 5.2
ka h-1 3.0
FaFg - 0.294/0.353/0.362
Ki,u,OATP1Bs μM 0.0846/0.100/0.111
Ki,u,MRP2 μM 0.87
β = 0.8
β = 0.5 β = 0.2
Parameters optimization by nonlinear least-squares fitting of CP-I bloodconcentration
Optimized parameters: CLint,all, FaFg (vsyn) and Ki,u,OATP1Bs
+RIF (600 mg)+RIF (300 mg)Control
-
PTV (β = 0.5, Ki,u = 0.22 μM)
33
Prediction of the effect of RIF on blood concentration-time profiles of statins
RSV (β = 0.5, Ki,u = 0.14 μM)
ATV (β = 0.5, Ki,u = 0.28 μM) FLV (β = 0.5, Ki,u = 0.35 μM)
+RIF (600 mg)+RIF (300 mg)Control
-
Summary
The PBPK modeling approach provides a deeper understanding of the mechanisms governing changes in the plasma conc. of an endogenous biomarker (CP-I) for OATP1Bs and MRP2 (CP-I) and enables complex analyses of the dose-dependent inhibitory effects of RIF on the hepatic OATP1Bs/MRP2-mediated transport of CP-I. It also lead to the successful prediction of RIF interaction with several probe substrates (statins) for OATP1Bs.
-
35
COI
I am a scientific advisory board member of the following companies.
1) SimCYP2) SEKISUI Medical
I am and have been a consultant of and collaborating with ca. 30 industries
-
31
Sugiyama Lab Main MembersTakashi Yoshikado（wet +dry, IVIVE DDI）Kota Toshimoto （dry,VCT(Virtual clinical study）Satoshi Koyama (wet + dry, IVIVE, DDI)Jieun.Park (wet + dry, IVIVE, DDI)
Wooin Lee (biochemistry of transporters,regulation of transporters)
Kim, Soo-Jin： (DDI, PGx, IVIVE)
Atsuko Tomaru (IVIVE, Bioanalysis wth LC/MS/MS)Aya Kiriake (IVIVE, transporter expression systems)Kiyoe Morita (IVIVE, isolated hepatocyte (suspension, plated) In-Soo Yoon (DDI, isolated hepatocytes (suspension, plated)
Kazuya Maeda, Hiroyuki Kusuhara (Univ of Tokyo)
Azusa Futatsugi (DDI, PGx)Keiko Ishigame (IVIVE, Bioanalysis) Hisako Motokawa(IVIVE, Bioanalysis)
RIKEN
PET-IVIVE consortiumPfizer, Daewoong(Korea), Abbie, Merck, Boehringer, BMS
Dr.Yasuyoshi Watanabe Labo, RIKEN Center for Life Science and RIKEN Center for Molecular Imaging Sciences
36
Secretaries;Sachie Sato, Aya Sonobe, Aya Miyamoto
スライド番号 1スライド番号 2 Drug-interaction between Cerivastatin and Gemfibrozil/CsA Examples of substrates for uptake/efflux transporters and enzymes (1) スライド番号 6スライド番号 7スライド番号 8スライド番号 9スライド番号 10スライド番号 11スライド番号 12スライド番号 13スライド番号 14スライド番号 15スライド番号 16スライド番号 17スライド番号 18スライド番号 19スライド番号 20スライド番号 21PBPK analyses of transporter/enzyme �mediated complex DDIBest simulation of CER vs CsA / CER vs GEMスライド番号 24スライド番号 25スライド番号 26スライド番号 27スライド番号 28スライド番号 29Endogenous probes will offer an option in assessment of pharmacokinetic DDI during drug development スライド番号 31スライド番号 32Prediction of the effect of RIF on blood concentration-time profiles of statinsSummaryスラ