evotec_Nov23_PanOmicsDriven - 13

90
of drugs fail in
late clinical development
US $
%
18%
drug withdrawals from
the market caused by DILI
testing earlier using more human-relevant cellbased
models. Major technological developments in
cellular biology such as widespread access to human
primary cells and human iPS cells along with liver
cell lines has advanced this research. Additionally,
further progress has been shown with more sophisticated
and physiologically relevant 3D liver models.
Robust and highly sensitive analytical techniques
have significantly advanced the predictive capabilities
of these approaches.
-
THE CHALLENGE OF DILI PREDICTION
Pharmaceutical companies have developed
various DILI screening strategies over the last
decade often consisting of liver cellular models with
mechanistic assays or endpoints such as:
Oxidative stress
Covalent binding
Cytochrome P450 TDI
Transporter interactions
2.6
ONLY
billion
and 15 years to develop a drug
50
DILI picked up
in animal studies
Mitochondrial dysfunction
Steatosis
Genotoxicity
Cytotoxicity
However, there is little consistency within
the industry on an optimal screening approach
and multiple assays are often required to capture
potential off-target effects. Limitations still
exist and more sensitive and specific techniques
are required to further improve our chances of
successfully identifying early safety liabilities.
MECHANISTIC UNDERSTANDING
IN SAFETY ASSESSMENT
Understanding the underlying mechanism of
drug-induced toxicity is vital in the prevention of
adverse effects. To address this, there is a need to
link molecular initiating events (MIE) to possible
mechanisms by assessing specific adverse outcome
pathway (AOP) perturbations and how these relate
%
13
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evotec_Nov23_PanOmicsDriven

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