Evaluation of Species-specific Drug-Induced Liver Injury

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 info@insphero.com l www.insphero.com

IC50 > 500 µmol/L IC50 > 500 µmol/L

1 1 0 1 0 0 1 0 0 0

S ita x s e n ta n (µ m o l/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

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

I C5 0 = -

IC 5 0 = -

IC50 = 190.9 µmol/L IC50 = 348.1 µmol/L

7 1 5 2 1 7 1 5 2 1 7 1 5 2 1

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

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

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

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

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

T im e (d a y s )

D o g /N P C

7 1 4 2 1 2 8

T im e (d a y s )

7 1 4 2 1 2 8

T im e (d a y s )

7 1 4 2 1 2 8

T im e (d a y s )

7 1 4 2 1 2 8

T im e (d a y s )

7 1 4 2 1 2 8

T im e (d a y s )

4 7 1 1 1 4 1 8 2 1 2 5 2 8

T im e (d a y s )

D o g /N P C

8 1 5 2 1

C u ltu re d a y

8 1 5 2 1

C u ltu re d a y

4 7 1 1 1 4 1 8 2 1 2 5 2 8

T im e (d a y s )

D o g /N P C

7 1 4 2 1 2 8

T im e (d a y s )

8 1 5 2 1

C u ltu re d a y

8 1 5 2 1

C u ltu re d a y

8 1 5 2 1

C u ltu re d a y

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

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

I C5 0 = -

IC 5 0 = -

1 1 0 1 0 0 1 0 0 0

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

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

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

I C5 0 = -

IC 5 0 = -

1 1 0 1 0 0 1 0 0 0

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

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

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

I C5 0 = -

IC 5 0 = -

1 1 0 1 0 0 1 0 0 0

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

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

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

I C5 0 = -

IC 5 0 = -

1 1 0 1 0 0 1 0 0 0

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

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

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

I C5 0 = -

IC 5 0 = -

1 1 0 1 0 0 1 0 0 0

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

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

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

I C5 0 = -

IC 5 0 = -

1 1 0 1 0 0 1 0 0 0

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

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

E n ta c a p o n e (µ m o l/L )

1 1 0 1 0 0 1 0 0 0

T o lc a p o n e (µ m o l/L )

0 .1 1 1 0 1 0 0

A m b ris e n ta n (µ m o l/L )

1 1 0 1 0 0 1 0 0 0

R o s ig lita z o n e (µ m o l/L )

0 .1 1 1 0 1 0 0 1 0 0 0

T ro g lita z o n e (µ m o l/L )

0 .1 1 1 0 1 0 0 1 0 0 0

K e to c o n a z o le (µ m o l/L )

0 .1 1 1 0 1 0 0 1 0 0 0

C h lo rp ro m a z in e (µ m o l/L )

0 .0 0 0 0 0 1 0 .0 0 0 1 0 .0 1 1

A f la to x in ( m o l/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

Evaluation of Species-specific Drug-Induced Liver Injury

Documents

Drug-Induced Liver Injury: Cascade of Events Leading to ... · International Journal of Molecular Sciences Review Drug-Induced Liver Injury: Cascade of Events Leading to Cell Death,

Drug Induced Liver Injury Network

129517154 Referat Drug Induced Liver Injury

Sterile Inflammation in Acetaminophen-induced Liver Injury Is

Clinicopathological features of He Shou Wu‐Induced Liver ... · persistent liver injury. Conclusions The main clinicopathological injury pattern of He Shou Wu-induced liver injury

Drug‑induced¢liver¢injury:¢Asia¢Paci¡c¢Association¢of

Makalah Drug Induced Liver Injury (DILI)

Recognizing Drug-Induced Liver Injury (DILI) in Exposed Populations

Case Report Metronidazole Induced Liver Injury: A Rare ...downloads.hindawi.com/journals/crigm/2013/568193.pdf · Case Report Metronidazole Induced Liver Injury: A Rare Immune Mediated

Acetaminophen-induced Liver Injury Alters Expression and ...dmd.aspetjournals.org/content/dmd/early/2020/02/24/dmd.119.0895… · Drug-induced liver injury (DILI) is a global medical

Drug Induced Liver Injury and Stevens Johnson …...Drug Induced Liver Injury and Stevens Johnson Syndrome SJS Symposium NIH, Bethesda, MD March 3-4, 2015 Jay H. Hoofnagle, M.D. Liver

Amiodarone-Induced Liver Injury and Cirrhosisacgcasereports.gi.org/files/2015/01/Buggey.pdf · Amiodarone-Induced Liver Injury and Cirrhosis ... with nearly one-quarter of patients

Diagnostic evaluation of suspected Drug-Induced Liver Injury · Paracetamol; ~50% of DILI) Idiosyncratic injury Drug-induced liver injury Kleiner et al. Hepatology 2014 Ciprofloxacin

Autoimmune Hepatitis or Drug Induced Liver Injury

Acute liver injury induced by weight-loss herbal supplementsvbvd.org/sites/default/files/publications/Herbalife_2.pdf · · 2017-07-05Acute liver injury induced by weight-loss herbal

Att induced liver injury

Diagnosis, management and prevention of drug-induced liver injury

Drug Induced Liver Injury (DILI) - Kaspen

Reduced Early Alcohol-Induced Liver Injury in CD14-Deficient Mice

Toward Predicting Drug-Induced Liver Injury: Parallel ... · Received February 26, 2015; accepted February 27, 2015 ABSTRACT Drug-induced liver injury (DILI) is an important cause