evotec_Nov23_PanOmicsDriven - 15

THE PROMISE OF NGS IN
DILI PREDICTION
The promise of transcriptomics and DILI
prediction became evident with the pioneering
studies in the early 2000's. These early studies
primarily focused on rodent in vivo studies which
were later shown to translate to surrogate gene
expression markers of DILI in human blood samples.
The current challenge is to detect DILI signatures
early from human in vitro cellular models. Evotec's
fully integrated platform has achieved significant
improvements in the prediction of DILI using AI
modelling of transcriptional data from primary
human hepatocytes. Following exposure of the
hepatocytes to 128 reference compounds, an
improved accuracy over established endpoint assays
has been demonstrated, increasing predictability
of DILI tox from 70% to 82%. The use of 3D cellular
models as well as greater mechanistic understanding
of the gene expression profiles from larger compound
libraries will enhance our understanding of
transcriptomics and its major role in toxicology
prediction.
Evotec is investing heavily in generating a
substantial reference database for DILI, using a large
set of drugs with annotation of DILI liabilities in a
number of biological test systems including 3D liver
microtissues. Combining this with transcriptomic
analysis and specialised data analysis tools will
further improve the prediction of DILI significantly
beyond 82%.
TRANSCRIPTOME & AI DELIVER SUPERIOR DILI PREDICTION
PanOmics
In vitro cellular
models e.g. liver
microtissues, PHH
Broad spectrum of
read-outs:
- Phenotypic
- Mechanistic
- Multiparametric
PanOmics analysis:
- Transcriptomics
- Proteomics
- Metabolomics
LEADING INDUSTRIAL DILI PREDICTION
PLATFORMS IN DIRECT COMPARISON
128 reference compounds tested in primary human hepatocytes (PHH).
In vitro assays vs. transcriptomics combined with AI
High-content imaging
Compound Cmax DILI in vivo HIAT assay Compound
acetaminophen 147.41 +VE
amiodarone
amitriptyline
amlodipine
atenolol
azathioprine
2.86 +VE
0.43 +VE
0.04 +VE
4.60 +VE
4.48 +VE
benzbromarone 13.96 +VE
bicalutamide
bosentan
bromfenac
carbamazepine
celecoxib
chloroquine
chlorpromazine
citalopram
clomipramine
clozapine
dasatinib
diclofenac
donepezil
erythromycin
fenofibrate
fluoxetine
flutamide
fluvastatin
gefitinib
gemfibrozil
haloperidol
ibuprofen
imatinib
imipramine
indomethacin
irbesartan
isoniazid
ketoconazole
lovastatin
metoclopramide
nefazodone
nifedipine
nimesulide
nitrofurantoin
nortriptyline
olanzapine
paroxetine
perhexiline
phenformin
pioglitazone
piroxicam
promethazine
rifabutin
risperidone
ritonavir
rosiglitazone
sertraline
simvastatin
sulindac
tamoxifen
1.96 +VE
6.04 +VE
19.77 +VE
43.24 +VE
2.68 +VE
0.48 +VE
0.90 +VE
0.26 +VE
0.49 +VE
1.77 +VE
0.61 +VE
9.28 +VE
0.11 +VE
7.24 +VE
18.57 +VE
0.28 +VE
4.36 +VE
0.58 +VE
0.21 +VE
185.36 +VE
0.04 +VE
302.05 +VE
4.40 +VE
0.50 +VE
7.44 +VE
3.51 +VE
75.74 +VE
12.11 +VE
0.02 +VE
0.40 +VE
3.62 +VE
0.28 +VE
20.07 +VE
15.15 +VE
0.81 +VE
0.08 +VE
0.15 +VE
2.11 +VE
0.63 +ve
3.01 +VE
9.82 +VE
0.28 +VE
0.69 +VE
0.07 +VE
15.00 +VE
1.06 +VE
0.08 +VE
0.02 +VE
24.66 +VE
0.73 +VE
-VE
+VE
-VE
+VE
-VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
-VE
+VE
+VE
+VE
+VE
-VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
-VE
+VE
+VE
-VE
+VE
+VE
+VE
+VE
+VE
-VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
-VE
+VE
+VE
+VE
+VE
+VE
-VE
amiodarone
amitriptyline
amlodipine
atenolol
warfarin
thioridazine
ticlopidine
tolcapone
troglitazone
verapamil
azathioprine
zafirlukast
zimelidine
atropine
betaine
Compound Cmax DILI in vivo HIAT assay Compound
acetaminophen 147.41 +VE
Cmax DILI in vivo HIAT assay
0.55
+
2.86 +VE
0.43 +VE
0.04 +VE
4.60 +VE
4.48 +VE
benzbromarone 13.96 +VE
bicalutamide
bosentan
bromfenac
zomepirac
amikacin
carbamazepine
celecoxib
chloroquine
chlorpromazine
citalopram
clomipramine
diclofenac
donepezil
fluoxetine
gefitinib
brompheniramine
caffeine
chlorpheniramine
dobutamine
dopamine
erythromycin
fenofibrate
droperidol
dutasteride
1.96 +VE
6.04 +VE
19.77 +VE
43.24 +VE
2.68 +VE
0.48 +VE
0.90 +VE
0.26 +VE
clozapinedextromethorphan 0.02
dasatinib
flutamidefenoldopam
fluvastatin
gemfibrozil
haloperidol
ibuprofen
imatinib
dexamethasone0.49 +VE
1.77 +VE
0.61 +VE
9.28 +VE
0.11 +VE
7.24 +VE
18.57 +VE
0.28 +VE
4.36 +VE
0.58 +VE
0.21 +VE
epinephrine
ergocalciferol
fexofenadine
flumazenil
folic acid
185.36 +VE
hydrocortisone 0.04 +VE
isoproterenol 302.05 +VE
imipramine
indomethacin
irbesartan
isoniazid
ketoconazole
lovastatin
metoclopramide
nefazodone
meclizine
minoxidil
nadolol
nifedipine
nimesulide
naloxone
neomycin
olanzapine
paroxetine
perhexiline
phenformin
pioglitazone
nitrofurantoin
nortriptyline
pimozide
pindolol
oxybutynin
isosorbide dinitrate 0.00
0.50 +VE
7.44 +VE
3.51 +VE
75.74 +VE
12.11 +VE
0.02 +VE
0.40 +VE
3.62 +VE
0.28 +VE
20.07 +VE
15.15 +VE
0.81 +VE
4.40 +VE
kanamycin
levocarnitine
liothyronine
loperamide
loratadine
59.50
85.70
0.01
0.01
0.07
0.03
1.19
0.61
0.00
0.44
0.02
phenoxybenzamine 0.19
0.08 +VE
phentolamine
physostigmine 0.15 +VE
2.11 +VE
plerixafor
piroxicampropantheline
promethazine
rifabutin
protriptyline
pyridoxine
risperidone
ritonavir
riboflavin
rosiglitazone
terazosin
thiamine
sulindac
sertralinetheophylline
simvastatin
tamoxifen
vinblastine
vitamin c
0.63 +ve
3.01 +VE
9.82 +VE
0.28 +VE
0.69 +VE
0.07 +VE
streptomycin 15.00 +VE
1.06 +VE
0.08 +VE
0.02 +VE
24.66 +VE
0.73 +VE
0.07
0.02
0.11
0.27
1.84
0.44
1.10
0.45
0.69
60.32
0.13
93.27
6.80
0.01
0.09
1.27
0.14
0.01
0.08
0.00
0.05
0.00
0.57
0.83
1.72
0.77
1.13
7.95
37.65
6.22
0.60
11.08
1.14
0.33
10.53
49.60
0.03
724.55
0.03
56.10
0.69
0.23
+
+
-VE
+VE+VE
-VE
+VE+VE
-VE
+VE+VE
+VE+VE
+VE+VE
+ve+VE
+VE
+VE
+VE
+VE
+VE
-VE
-VE
-VE
-VE
-VE
-VE-VE
+VE
+VE
+VE
+VE
-VE
-VE
-VE
-VE
-VE-VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-ve
-VE
-VE-VE
+VE
+VE
-VE
-VE
-VE-VE
+VE
+VE
+VE
+VE
+VE
-VE
-VE
-VE
-VE
-VE
-VE-VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE-VE
+VE
+VE
+VE
+VE
+VE
-VE
-VE
-VE
-VE
-VE
-VE-VE
tolcapone
+VE
-VE
+VE
+VE
+VE
warfarin
+VE
+VE
thioridazine
ticlopidine
troglitazone
verapamil
+VE
zafirlukast
zimelidine
+VE
+VE
-VE
+VE
-VE
+VE
+VE
-VE
-VE
+VE
-VE
-VE
atropine
betaine
zomepirac
amikacin
CompoundCmax DILI in vivo HIAT assay
0.55
acetaminophen
7.95
amiodarone
37.65
amlodipine
atenolol0.60
11.08
+VE
+VE
amitriptyline +VE
6.22
+VE
+VE
azathioprine +VE
1.14
benzbromarone+VE
0.33
bicalutamide +VE
bosentan10.53
49.60
bromfenac
0.03
chlorpheniraminecitalopram
dexamethasone
dextromethorphan 0.02
dobutamine
dopamine
droperidol
+VE
-VE
-VE
-VE
dutasteride
epinephrine
ergocalciferol
fenoldopam
-VE
-VE
+VE
fexofenadine
flumazenil
folic acid
-VE
+VE
levocarnitine
liothyronine
loperamide
loratadine
meclizine
minoxidil
nadolol
-VE
-VE
-VE
plerixafor
-VE
-VE
-VE
+VE
+VE
+VE
riboflavin
-VE
-VE
-VE
-VE
+VE
-VE
+VE
-VE
-VE
hydrocortisone
isoproterenol
-VE
-VE
-VE
-VE
-VE
-VE
-VE
+VE
-VE
naloxone
neomycin
oxybutynin
-VE
clomipramine -VE
-VE
0.23
clozapine
1.27
dasatinib
0.14
diclofenac
0.01
donepezil
0.08
flutamide
0.57
gemfibrozil
0.77
1.72
haloperidol
1.13
isosorbide dinitrate 0.00
kanamycin
ibuprofen
imatinib
59.50
isoniazid
0.07
imipramine
85.70
irbesartan
0.01
lovastatin
1.19
fenofibrate
0.05
fluoxetine
0.00
fluvastatin
gefitinib0.83
-VE
-VE
-VE
erythromycin -VE
0.00
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
indomethacin -ve
0.01
-VE
-VE
ketoconazole -VE
0.03
metoclopramide
0.61
nefazodone
0.00
nifedipine
0.44
phenoxybenzamine 0.19
phentolamine
physostigmine
pimozide
pindolol
propantheline
protriptyline
pyridoxine
streptomycin
terazosin
theophylline
thiamine
vinblastine
vitamin c
promethazine -VE
0.45
1.10
rifabutin
0.69
ritonavir
0.13
sulindac
0.09
risperidone
60.32
simvastatin
0.01
tamoxifen
-VE
-VE
-VE
rosiglitazone -VE
sertraline93.27
6.80
-VE
-VE
-VE
-VE
nimesulide
0.02
olanzapine
0.02
paroxetine
0.11
nortriptyline
0.07
perhexiline
0.27
phenformin
1.84
-VE
-VE
-VE
-VE
-VE
nitrofurantoin-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
pioglitazone
piroxicam0.44
chlorpromazine
0.69
56.10
brompheniraminechloroquine
caffeine
carbamazepine
celecoxib724.55
0.03
+ve
-VE
-VE
-VE
-VE
-VE
-VE
147.41+VE
2.86 +VE
0.43 +VE
0.04 +VE
4.60 -VE
4.48 +VE
13.96 +VE
1.96 +VE
6.04 +VE
19.77 +VE
43.24 -VE
2.68 +VE
0.48 -VE
0.90 +VE
0.26 +VE
0.49 -VE
1.77 -VE
0.61 +VE
9.28 -VE
0.11 -VE
7.24 +VE
18.57 -VE
0.28 -VE
4.36 -VE
0.58 -VE
0.21 -VE
185.36+VE
0.04 -VE
302.05+VE
4.40 -VE
0.50 -VE
7.44 -VE
3.51 -VE
75.74 -VE
12.11 -VE
0.02 -VE
0.40 +VE
3.62 -VE
0.28 -VE
20.07 -VE
15.15 -VE
0.81 -VE
0.08 -VE
0.15 -VE
2.11 +VE
0.63 +VE
3.01 +VE
9.82 -VE
0.28 +VE
0.69 -VE
0.07 -VE
15.00 -VE
1.06 -VE
0.08 -VE
0.02 -VE
24.66 +VE
0.73 -VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+ve
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
Transcriptome analysis
Avg Cmax DILI in vivo Transc & AI Compound
acetaminophen
amiodarone+VE
Compound
-VE
amitriptyline+VE
amlodipine+VE
atenolol -VE
azathioprine+VE
+VE
carbamazepine
celecoxib+VE
+VE
+VE
chlorpromazine
citalopram
+VE
+VE
-VE
+VE
+VE
clomipramine
clozapine+VE
dasatinib+VE
diclofenac
donepezil-VE
erythromycin+VE
+VE
+VE
fenofibrate
fluoxetine
flutamide+VE
fluvastatin
+VE
gefitinib +VE
gemfibrozil+VE
haloperidol+VE
ibuprofen
+VE
imatinib +VE
imipramine+VE
indomethacin+VE
irbesartan
+VE
isoniazid +VE
ketoconazole+VE
+VE metoclopramide
nefazodone+VE
nifedipine
nimesulide
olanzapine
paroxetine
nitrofurantoin
nortriptyline+VE
+VE
+VE
+VE
-VE
+VE
perhexiline+VE
phenformin+VE
pioglitazone+VE
piroxicam+VE
promethazine+VE
rifabutin +VE
-VE
risperidone
ritonavir +VE
rosiglitazone+VE
sertraline+VE
simvastatin+VE
sulindac +VE
tamoxifen
+VE
chloroquine
benzbromarone
bicalutamide+VE
bosentan+VE
bromfenac
ticlopidine
0.43
147.41
2.86
tolcapone
0.04
verapamil
warfarin
13.96
4.48
zafirlukast
1.96
zimelidine
6.04
amikacin
43.24
atropine
2.68
betaine
0.48
0.90
0.26
zomepirac
19.77
troglitazone
4.60
Avg Cmax DILI in vivo Transc & AI Compound
thioridazine
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
brompheniramine+VE
caffeine
+VE
chlorpheniramine+VE
0.49
dexamethasone
1.77
dobutamine
9.28
dopamine
0.11
droperidol
7.24
fexofenadine +VE
flumazenil
folic acid
4.36
0.58
0.21
hydrocortisone
302.05
185.36
0.04
kanamycin
7.44
lovastatin+VE meclizine
0.40
+VE minoxidil
3.62
nadolol
0.28
naloxone
20.07
15.15
0.81
pimozide
0.63
pindolol
3.01
neomycin
oxybutynin
loratadine
0.02
75.74
12.11
+VE
+VE
+VE
isoproterenol +VE
4.40
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
levocarnitine +VE
3.51
liothyronine
loperamide
isosorbide dinitrate
0.50
dutasteride
18.57
epinephrine
0.28
dextromethorphan
0.61
+VE
+VE
+VE
+VE
+VE
+VE
+VE
ergocalciferol +VE
fenoldopam +VE
0.55
7.95
6.22
0.60
1.14
0.33
0.03
0.03
0.69
0.23
0.02
1.27
0.14
0.01
0.08
0.00
0.05
0.00
0.57
0.83
1.72
0.77
1.13
0.00
phenoxybenzamine+VE
0.08
phentolamine+VE
0.15
physostigmine+VE
2.11
plerixafor
9.82
0.07
+VE
+ve
+VE
propantheline+VE
0.28
protriptyline +VE
0.69
pyridoxine
riboflavin
15.00
terazosin
0.08
thiamine
24.66
vitamin c
+VE
+VE
streptomycin +VE
1.06
+VE
theophylline +VE
0.02
vinblastine
0.73
+VE
+VE
+VE
0.01
0.01
0.07
0.03
1.19
0.61
0.00
0.44
0.02
0.19
0.07
0.02
0.11
0.27
1.84
0.44
1.10
0.45
0.69
0.13
6.80
0.01
0.09
-VE
+VE
37.65+VE
+VE
-VE
11.08+VE
+VE
+VE
10.53+VE
49.60+VE
+VE
724.55+VE
+VE
56.10+VE
-VE
+VE
+VE
+VE
+VE
-VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
59.50+VE
85.70+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
-VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
-VE
60.32+VE
+VE
93.27+VE
+VE
+VE
+VE
ticlopidine
tolcapone
+VE
+VE
+VE
+VE
+VE
warfarin
+VE
+VE
zafirlukast
zimelidine
+ve
-VE
-VE
atropine
betaine-VE
chlorpheniramine -VE
dexamethasone
dextromethorphan
dobutamine
dopamine
droperidol
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
dutasteride
epinephrine
ergocalciferol
fenoldopam
-VE
-VE
-VE
fexofenadine
flumazenil
folic acid
-VE
-VE
levocarnitine
liothyronine
loperamide
loratadine
+VE meclizine
+VE minoxidil
nadolol
-VE
-VE
-VE
plerixafor
-VE
-VE
-VE
-VE
-VE
-VE
riboflavin
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
hydrocortisone
isoproterenol
-VE
-VE
-ve
-VE
-VE
-VE
-VE
-VE
-VE
naloxone
neomycin
oxybutynin
-VE
isosorbide dinitrate
kanamycin
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
troglitazone
verapamil
+VE
zomepirac
amikacin
Avg Cmax DILI in vivo Transc & AI
thioridazine
+VE
+VE
+VE
-VE
+VE
+VE
-VE
Avg Cmax DILI in vivo Transc & AI
0.55
7.95
+VE 37.65
6.22
0.60
+VE 11.08
1.14
0.33
+VE 10.53
-VE 49.60
0.03
brompheniramine-VE
caffeine
+VE 724.55
0.03
-VE 56.10
0.69
0.23
0.02
1.27
0.14
0.01
0.08
0.00
0.05
0.00
0.57
0.83
1.72
0.77
1.13
0.00
phenoxybenzamine
phentolamine
physostigmine
pimozide
pindolol
propantheline
protriptyline
pyridoxine
streptomycin
terazosin
theophylline
thiamine
vinblastine
vitamin c
-VE 59.50
-VE 85.70
0.01
0.01
0.07
0.03
1.19
0.61
0.00
0.44
0.02
0.19
0.07
0.02
0.11
0.27
1.84
0.44
1.10
0.45
0.69
-VE 60.32
0.13
-VE
-VE 93.27
6.80
0.01
0.09
-VE
-VE
-VE
-VE
-VE
-VE
-VE
+VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
+VE
-VE
-VE
-VE
+VE
-VE
-VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+VE
+ve
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
-VE
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PanHunter
Data base of
toxicology profiles
Integrated AI to
enhance predictive
power
Unrivalled
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Comprehensive data
analysis platform
Integrated service
Accuracy: 70%
Accuracy: 82%
Superior accuracy over current in vitro assay approach plus additional mechanistic insight gained from transcriptomics.
15
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evotec_Nov23_PanOmicsDriven

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