In vitroTox - Cerep

ADR panel
Identifying Potential Adverse
10
Drug Reactions (ADRs) 9
Cerep’s ADR Panels offer a client the ability to focus on
specific body systems suggested by results seen in their
preclinical or clinical studies. Cerep’s unique experience
with pharmacological screening of drugs and other
reference compounds has allowed to offer small
affordable panels of assays that cover serious ADRs that
are either directly or statistically associated with different
body systems.
ADR Profiles by Body System
pIC 50
8
7
6
5
4
3
Restlessness, lethargy
Depression, Gi disorder
Ataxia, amnesia, agitation
ASSAYS
Figure 1. ADRs associated with a test compound’s individual
pharmacology assay hits.
Many drug ADRs are linked to off-target activities at a great variety of cellular receptors and enzymes. Cerep has created a series
of assay profiles, each oriented to the ADRs of six specific body systems: Blood, Liver, Kidney, CNS, Cardiovascular and Lung.
The targets are chosen for each profile on the basis of statistical associations derived from Cerep’s proprietary BioPrint ® and from
available ADR databases.
Table 1. List of targets for 6 organ systems
Cyst
Blood
CNS
CV
Kidney
Liver
Lung
Assay Name
Ref.
5-HT transporter 0439 l l l
5-HT1A 0131 l
5-HT1B 0132 l
5-HT2A 0471 l l l
5-HT2B 1333 l
5-HT2C 1003 l l l
5-HT3 0411 l
5-HT4e 0501 l
5-HT7 0144 l
A2B 0005 l
A3 0006 l
ACE 3441 l l l l l
acetylcholinesterase 0363 l l l l
adenylyl cyclase 3002 l l l
alpha1A 2338 l l
alpha2A 1669 l l
alpha2B 1344 l l l l
alpha2C 1682 l
AR 0933 l l l
AT1 0024 l
ATPase (Na+/K+) 2009 l l
beta1 0018 l l l
beta2 0020 l l
BZD (central) 0028 l
Ca2+ L (diltiazem site) 0162 l
carbonic anhydrase II 2572 l l
CB1 0036 l
Cl- channel (GABA-gated) 0170 l
constitutive NOS (endothelial) 0197 l
COX2 0727 l l l l l
D1 0044 l l l
D2S 1322 l
D2S 1322 l
D3 0048 l
D4.4 0049 l l l
delta2 (DOP) 0114 l l
dipeptidyl peptidase IV (DPP-IV) 2942 l
dopamine transporter 0052 l
sales@cerep.com l www.cerep.com
Blood
CNS
CV
Kidney
Liver
Lung
Assay Name
Ref.
elastase 0183 l
ERa 0484 l l l
ERK2 (P42mapk) 2878 l
ETB 0056 l
FLT-1 kinase (VEGFR1) 3068 l
FP 1979 l
GABA transaminase 0461 l
GABA transporter 0060 l
GABAA1 (a1,b2,γ2) 3051 l
GR 0469 l
GSK3a 2842 l l
H1 0870 l l
H2 1208 l l l l
hERG (membrane preparation) 1868 l
kappa (KOP) 1971 l
M2 0093 l l l
M4 0096 l
M5 0097 l l
MAO-A 0443 l l l
motilin 0470 l l
MT3 (ML2) 0088 l l l
mu (MOP) 0118 l
N muscle-type 0936 l
Na+ site 2 0169 l l l l l
NK2 0102 l l
NMDA 0066 l l l
norepinephrine transporter 0355 l l
PCP 0124 l
PDE3A 2432 l
PLC 2837 l
PTH1 2660 l
sigma (non-selective) 3500 l
SKCa 0167 l l
TNF-a 0076 l l
TP (TXA2/PGH2) 0001 l l
tyrosine hydroxylase 0214 l l
UT 1386 l l
In vitro Tox

ADR panel
Table 2. List of serious ADR drug for 6 organ systems
CNS
Asthenia
Ataxia
Cholinergic toxicity
Coma
Confusion
Convulsion
Depression
Emesis
Extrapyramidal symptoms
Hyperpyrexia
Hypomotility
Nausea
Neuroleptic malignant
syndrome
Neurotoxicity neuropathy
Parkinsonism
Sedation
Seizures
Tardive dyskinesia
Tremors
Vertigo
CV
Atrioventricular block
Bradycardia
Cardiac arrest
Cardiac failure
Cerebrovascular dysfunction
Congestive heart failure
Coronary vascular damage
Dysrhythmias
Heart block
Hypertension
Hypotension
Ischemia
Myocardial damage
Myocardial infarction
Sudden cardiac death
Tachycardia
Torsade de pointes
Vasoconstriction
Ventricular arrhythmias
LIVER
LUNG
Cholestasis
Hepatic and hepatobiliary
disorders
Hepatitis
Hepatocellular damage
Hepatopulmonary syndrome
Hepatotoxicity
Jaundice
Airway hyperreactivity
Bronchial disorders
Fibrosis
Granulocyte infiltration
Interstitial pneumonia
Thromboembolism
Vascular pulmonary disorders
BLOOD
KIDNEY
Anemia
Azotemia
Bilirubinemia
Blood autoimmune disorders
Blood dyscrasia
Hematuria
Hemolytic anemia
Hyperbilirubinaemia
Neutropenia
Peripheral ischemia
Platelet aggregation
Porphyria
Red blood cell disorder
Uremia
Diabetic complications
Kidney failure
Nephrotoxicity
Protein present in urine
Renal dysfunction
Urinary tract disorder
Panel Design
➥ Known association of individual targets with serious ADRs
l ADR Databases: DART 1&2 and DITOP 3&4 – Identification of targets already known to be linked to specific ADRs
l Literature – Assay selection based on literature reviewing the mechanisms of action for individual ADRs
➥ Statistical association of individual targets with serious ADRs using information from Cerep’s proprietary BioPrint ® Database
l Using BioPrint ® , targets are selected based on statistical associations between individual targets and individual ADRs.
Chi-square analysis was performed to identify statistically significant correlations in a matrix of >150 assays by >800 ADR terms 5 .
Over 5,000 significant in vitro assay-ADR associations were found covering over 100 assays. Close examination of this set of
associations yields many results that are consistent with known pharmacology and many others that appear to be novel.
Figure 2. M3 and “abnormal visual accommodation”
IC 50
BinRange (nM) / BinHits
ADR negative ADR positive Baseline
0 to 99 (n=26)
100 to 499 (n=14)
500 to 999 (n=14)
1,000 to 4,999 (n=32)
5,000 to 9,999 (n=22)
10,000 to 49,999 (n=41)
50,000+ (n=894)
-100 -75 -50 -25 0 25 50 75 100
Percentage of hits
Figure 2 shows the significant statistical association between
in vitro binding to the M3 muscarinic receptor and
the in vivo ADR “abnormal visual accommodation”. Seven
IC 50 activity bins are found on the y-axis ranging from the
0-99 nM bin to the greater-than-50,000 nM bin which is
the default bin for the non-hits. The number of compounds
in each bin is indicated. The blue and red bars shown with
each bin represent the percentage of compounds in that
bin that are positive (blue) or negative (red) for the ADR in
question. This figure illustrates the association of “abnormal
visual accommodation” with the M3 muscarinic receptor.
The baseline frequency of this ADR is 6.44% while nearly
half of the drugs with M3 hits in the