Embed Size (px)
Citation preview
Evaluation of Species-specific Drug-Induced Liver Injury in
3D Rat, Dog, Monkey and Human Liver Microtissues
Monika Kijanska, Katrin Rössger and Simon Messner
InSphero AG, Schlieren, Switzerland
InSphero AG l Wagistrasse 27, CH-8952 Schlieren, Switzerland l Phone: +41 44 515 04 90 l [email protected] l www.insphero.com
•
o
o
o
o
o
•
•
•
•
•
•
IC50 > 500 µmol/L IC50 > 500 µmol/L
1 1 0 1 0 0 1 0 0 0
0
5 0
1 0 0
1 5 0
S ita x s e n ta n (µ m o l/L )
Ce
ll v
iab
ilit
y
(% o
f c
on
tro
l)
C y n o /N P C
D o g /N P C
IC 5 0 = m o l/L1 9 0 .9
IC 5 0 m o l/L54 7.6
IC 5 0 = m ol / L3 4 8 .1
Mul ti d o n o r/N P C
f e mal e ra tL iM T /N P C
male ra tL iM T /N P C
I C5 0 = -
IC 5 0 = -
1 1 0 1 0 0 1 0 0 0
0
5 0
1 0 0
1 5 0
S ita x s e n ta n (µ m o l/L )
Ce
ll v
iab
ilit
y
(% o
f c
on
tro
l)
C y n o /N P C
D o g /N P C
IC 5 0 = m o l/L1 9 0 .9
IC 5 0 m o l/L54 7.6
IC 5 0 = m ol / L3 4 8 .1
Mul ti d o n o r/N P C
f e mal e ra tL iM T /N P C
male ra tL iM T /N P C
I C5 0 = -
IC 5 0 = -
IC50 = 190.9 µmol/L IC50 = 348.1 µmol/L
- O
•
•
•
•
•
•
•
•
7 1 5 2 1 7 1 5 2 1 7 1 5 2 1
0
5
1 0
1 5
AT
P (
pm
ol/
MT
)
C y n o /
IP H N _ 0 3
C y n o /
IP H N _ 0 1C y n o
o n ly
T im e (d a y s )
7 1 5 2 1 7 1 5 2 1 7 1 5 2 1
0
5
1 0
1 5
AT
P (
pm
ol/
MT
)
C y n o /
IP H N _ 0 3
C y n o /
IP H N _ 0 1C y n o
o n ly
T im e (d a y s )
7 1 5 2 1 7 1 5 2 1 7 1 5 2 1
0
5
1 0
1 5
AT
P (
pm
ol/
MT
)
C y n o /
IP H N _ 0 3
C y n o /
IP H N _ 0 1C y n o
o n ly
T im e (d a y s )
4 7 1 1 1 4 1 8 2 1 2 5 2 8
0
1 0
2 0
3 0
4 0
5 0
6 0
AT
P (
pm
ol/
MT
)
T im e (d a y s )
D o g /N P C
4 7 1 1 1 4 1 8 2 1 2 5 2 8
0
1 0
2 0
3 0
4 0
5 0
6 0
AT
P (
pm
ol/
MT
)
T im e (d a y s )
D o g /N P C
4 7 1 1 1 4 1 8 2 1 2 5 2 8
0
1 0
2 0
3 0
4 0
5 0
6 0
AT
P (
pm
ol/
MT
)
T im e (d a y s )
D o g /N P C
7 1 4 2 1 2 8
0
5
1 0
1 5
2 0
AT
P (
pm
ol/
MT
)
T im e (d a y s )
7 1 4 2 1 2 8
0
5
1 0
1 5
2 0
AT
P (
pm
ol/
MT
)
T im e (d a y s )
7 1 4 2 1 2 8
0
5
1 0
1 5
2 0
AT
P (
pm
ol/
MT
)
T im e (d a y s )
7 1 4 2 1 2 8
0
5
1 0
1 5
2 0
AT
P (
pm
ol/
MT
)
T im e (d a y s )
7 1 4 2 1 2 8
0
5
1 0
1 5
2 0
AT
P (p
mo
l/M
T)
T im e (d a y s )
4 7 1 1 1 4 1 8 2 1 2 5 2 8
0
1 0
2 0
3 0
4 0
5 0
6 0
AT
P (
pm
ol/
MT
)
T im e (d a y s )
D o g /N P C
8 1 5 2 1
0
5
1 0
1 5
C u ltu re d a y
AT
P
(pm
ol/
MT
)
8 1 5 2 1
0
5
1 0
1 5
C u ltu re d a y
AT
P
(p
mo
l/M
T)
4 7 1 1 1 4 1 8 2 1 2 5 2 8
0
1 0
2 0
3 0
4 0
5 0
6 0
AT
P (
pm
ol/
MT
)
T im e (d a y s )
D o g /N P C
7 1 4 2 1 2 8
0
5
1 0
1 5
2 0
AT
P (
pm
ol/
MT
)
T im e (d a y s )
8 1 5 2 1
0
5
1 0
1 5
C u ltu re d a y
AT
P
(pm
ol/
MT
)
8 1 5 2 1
0
5
1 0
1 5
C u ltu re d a y
AT
P
(pm
ol/
MT
)
8 1 5 2 1
0
5
1 0
1 5
C u ltu re d a y
AT
P
(pm
ol/
MT
)
IC50 > 50 µmol/L
Human Dog Monkey Rat
Ambrisentan 0,79 50 N >63 >63 >63 >63
Sitaxsentan 28,6 500 Y 6,6 12,2 >18 >18
Entacapone 3,3 500 N >76 52,5 >151 >151
Tolcapone 47,6 100 Y 2,5 0,8 1,8 1,3
Rosiglitazone 1 200 Y (rare) >100 >200 >200 125,4
Troglitazone 6,4 500 Y 9,2 >7.8 >7.8 >7.8
Chlorpromazine 0,9 200 Y 22,6 29,4 15,1 20,1
Ketoconazole 11,3 100 Y 0,4 1 0,3 0,8
Cmax [µM]CompoundMOS (human Cmax/IC50) Top conc.
Tested
Toxicity
in clinic?
1 1 0 1 0 0 1 0 0 0
0
5 0
1 0 0
1 5 0
S ita x s e n ta n (µ m o l/L )
Ce
ll v
iab
ilit
y
(% o
f c
on
tro
l)
C y n o /N P C
D o g /N P C
IC 5 0 = m o l/L1 9 0 .9
IC 5 0 m o l/L54 7.6
IC 5 0 = m ol / L3 4 8 .1
Mul ti d o n o r/N P C
f e mal e ra tL iM T /N P C
male ra tL iM T /N P C
I C5 0 = -
IC 5 0 = -
1 1 0 1 0 0 1 0 0 0
0
5 0
1 0 0
1 5 0
S ita x s e n ta n (µ m o l/L )
Ce
ll v
iab
ilit
y
(% o
f c
on
tro
l)
C y n o /N P C
D o g /N P C
IC 5 0 = m o l/L1 9 0 .9
IC 5 0 m o l/L54 7.6
IC 5 0 = m ol / L3 4 8 .1
Mul ti d o n o r/N P C
f e mal e ra tL iM T /N P C
male ra tL iM T /N P C
I C5 0 = -
IC 5 0 = -
IC50 > 100 µmol/L IC50 > 200 µmol/L IC50 > 200 µmol/L IC50 = 125.3 µmol/L
IC50 > 50 µmol/L IC50 > 50 µmol/L
IC50 > 50 µmol/L
1 1 0 1 0 0 1 0 0 0
0
5 0
1 0 0
1 5 0
S ita x s e n ta n (µ m o l/L )
Ce
ll v
iab
ilit
y
(% o
f c
on
tro
l)
C y n o /N P C
D o g /N P C
IC 5 0 = m o l/L1 9 0 .9
IC 5 0 m o l/L54 7.6
IC 5 0 = m ol / L3 4 8 .1
Mul ti d o n o r/N P C
f e mal e ra tL iM T /N P C
male ra tL iM T /N P C
I C5 0 = -
IC 5 0 = -
1 1 0 1 0 0 1 0 0 0
0
5 0
1 0 0
1 5 0
S ita x s e n ta n (µ m o l/L )
Ce
ll v
iab
ilit
y
(% o
f c
on
tro
l)
C y n o /N P C
D o g /N P C
IC 5 0 = m o l/L1 9 0 .9
IC 5 0 m o l/L54 7.6
IC 5 0 = m ol / L3 4 8 .1
Mul ti d o n o r/N P C
f e mal e ra tL iM T /N P C
male ra tL iM T /N P C
I C5 0 = -
IC 5 0 = -
IC50 = 58.7 µmol/L
IC50 > 250 µmol/L
1 1 0 1 0 0 1 0 0 0
0
5 0
1 0 0
1 5 0
S ita x s e n ta n (µ m o l/L )
Ce
ll v
iab
ilit
y
(% o
f c
on
tro
l)
C y n o /N P C
D o g /N P C
IC 5 0 = m o l/L1 9 0 .9
IC 5 0 m o l/L54 7.6
IC 5 0 = m ol / L3 4 8 .1
Mul ti d o n o r/N P C
f e mal e ra tL iM T /N P C
male ra tL iM T /N P C
I C5 0 = -
IC 5 0 = -
1 1 0 1 0 0 1 0 0 0
0
5 0
1 0 0
1 5 0
S ita x s e n ta n (µ m o l/L )
Ce
ll v
iab
ilit
y
(% o
f c
on
tro
l)
C y n o /N P C
D o g /N P C
IC 5 0 = m o l/L1 9 0 .9
IC 5 0 m o l/L54 7.6
IC 5 0 = m ol / L3 4 8 .1
Mul ti d o n o r/N P C
f e mal e ra tL iM T /N P C
male ra tL iM T /N P C
I C5 0 = -
IC 5 0 = -
IC50 = 173.4 µmol/L IC50 > 500 µmol/L IC50 > 500 µmol/L IC50 > 60.5 µmol/L
1 1 0 1 0 0 1 0 0 0
0
5 0
1 0 0
1 5 0
S ita x s e n ta n (µ m o l/L )
Ce
ll v
iab
ilit
y
(% o
f c
on
tro
l)
C y n o /N P C
D o g /N P C
IC 5 0 = m o l/L1 9 0 .9
IC 5 0 m o l/L54 7.6
IC 5 0 = m ol / L3 4 8 .1
Mul ti d o n o r/N P C
f e mal e ra tL iM T /N P C
male ra tL iM T /N P C
I C5 0 = -
IC 5 0 = -
1 1 0 1 0 0 1 0 0 0
0
5 0
1 0 0
1 5 0
S ita x s e n ta n (µ m o l/L )
Ce
ll v
iab
ilit
y
(% o
f c
on
tro
l)
C y n o /N P C
D o g /N P C
IC 5 0 = m o l/L1 9 0 .9
IC 5 0 m o l/L54 7.6
IC 5 0 = m ol / L3 4 8 .1
Mul ti d o n o r/N P C
f e mal e ra tL iM T /N P C
male ra tL iM T /N P C
I C5 0 = -
IC 5 0 = -
IC50 = 118.0 µmol/L IC50 = 40.3 µmol/L IC50 = 85.4 µmol/L
1 1 0 1 0 0 1 0 0 0
0
5 0
1 0 0
1 5 0
S ita x s e n ta n (µ m o l/L )
Ce
ll v
iab
ilit
y
(% o
f c
on
tro
l)
C y n o /N P C
D o g /N P C
IC 5 0 = m o l/L1 9 0 .9
IC 5 0 m o l/L54 7.6
IC 5 0 = m ol / L3 4 8 .1
Mul ti d o n o r/N P C
f e mal e ra tL iM T /N P C
male ra tL iM T /N P C
I C5 0 = -
IC 5 0 = -
1 1 0 1 0 0 1 0 0 0
0
5 0
1 0 0
1 5 0
S ita x s e n ta n (µ m o l/L )
Ce
ll v
iab
ilit
y
(% o
f c
on
tro
l)
C y n o /N P C
D o g /N P C
IC 5 0 = m o l/L1 9 0 .9
IC 5 0 m o l/L54 7.6
IC 5 0 = m ol / L3 4 8 .1
Mul ti d o n o r/N P C
f e mal e ra tL iM T /N P C
male ra tL iM T /N P C
I C5 0 = -
IC 5 0 = -
IC50 = 5.0 µmol/L IC50 = 11.7 µmol/L IC50 = 3.4 µmol/L IC50 = 9.1 µmol/L
1 1 0 1 0 0 1 0 0 0
0
5 0
1 0 0
1 5 0
S ita x s e n ta n (µ m o l/L )
Ce
ll v
iab
ilit
y
(% o
f c
on
tro
l)
C y n o /N P C
D o g /N P C
IC 5 0 = m o l/L1 9 0 .9
IC 5 0 m o l/L54 7.6
IC 5 0 = m ol / L3 4 8 .1
Mul ti d o n o r/N P C
f e mal e ra tL iM T /N P C
male ra tL iM T /N P C
I C5 0 = -
IC 5 0 = -
1 1 0 1 0 0 1 0 0 0
0
5 0
1 0 0
1 5 0
S ita x s e n ta n (µ m o l/L )
Ce
ll v
iab
ilit
y
(% o
f c
on
tro
l)
C y n o /N P C
D o g /N P C
IC 5 0 = m o l/L1 9 0 .9
IC 5 0 m o l/L54 7.6
IC 5 0 = m ol / L3 4 8 .1
Mul ti d o n o r/N P C
f e mal e ra tL iM T /N P C
male ra tL iM T /N P C
I C5 0 = -
IC 5 0 = -
IC50 = 20.3 µmol/L IC50 = 29.4 µmol/L IC50 = 13.6 µmol/L IC50 = 18.7 µmol/L
1 1 0 1 0 0 1 0 0 0
0
5 0
1 0 0
1 5 0
E n ta c a p o n e (µ m o l/L )
Ce
ll v
iab
ilit
y
(% o
f c
on
tro
l)
1 1 0 1 0 0 1 0 0 0
0
5 0
1 0 0
1 5 0
T o lc a p o n e (µ m o l/L )
Ce
ll v
iab
ilit
y
(% o
f c
on
tro
l)
0 .1 1 1 0 1 0 0
0
5 0
1 0 0
1 5 0
A m b ris e n ta n (µ m o l/L )
Ce
ll v
iab
ilit
y
(% o
f c
on
tro
l)
1 1 0 1 0 0 1 0 0 0
0
5 0
1 0 0
1 5 0
S ita x s e n ta n (µ m o l/L )
Ce
ll v
iab
ilit
y
(% o
f c
on
tro
l)
1 1 0 1 0 0 1 0 0 0
0
5 0
1 0 0
1 5 0
R o s ig lita z o n e (µ m o l/L )
Ce
ll v
iab
ilit
y
(% o
f c
on
tro
l)
0 .1 1 1 0 1 0 0 1 0 0 0
0
5 0
1 0 0
1 5 0
T ro g lita z o n e (µ m o l/L )
Ce
ll v
iab
ilit
y
(% o
f c
on
tro
l)
0 .1 1 1 0 1 0 0 1 0 0 0
0
5 0
1 0 0
1 5 0
K e to c o n a z o le (µ m o l/L )
Ce
ll v
iab
ilit
y
(% o
f c
on
tro
l)
0 .1 1 1 0 1 0 0 1 0 0 0
0
5 0
1 0 0
1 5 0
C h lo rp ro m a z in e (µ m o l/L )
Ce
ll v
iab
ilit
y
(% o
f c
on
tro
l)
0 .0 0 0 0 0 1 0 .0 0 0 1 0 .0 1 1
0
5 0
1 0 0
1 5 0
A f la to x in ( m o l/L )
Ce
ll v
iab
ilit
y
(% o
f c
on
tro
l)
D o g IC 5 0 = 0 .0 1 6 m ol/L
H u m a n IC 5 0 = 0 .1 1 1 m ol/L
•
•
•
Red
Green
White
