Relationships between the Structure and Severe Drug-Induced Liver Injury for Low, Medium, and High Doses of Drugs

Assessment of structure–activity
relationships (SARs) for
predicting severe drug-induced liver injury (DILI) is essential since in vivo and in vitro preclinical methods
cannot detect many druglike compounds disrupting liver functions.
To date, plenty of SAR models for the prediction of DILI have been
developed; however, none of them considered the route of drug administration
and daily dose, which may introduce significant bias into prediction
results. We have created a dataset of 617 drugs with parenteral and
oral administration routes and consistent information on DILI severity.
We have found a clear relationship between route, dose, and DILI severity.
According to SAR, nearly 40% of moderate- and non-DILI-causing drugs
would cause severe DILI if they were administered at high oral doses.
We have proposed the following approach to predict severe DILI. New
compounds recommended to be used at low oral doses (<∼10
mg daily), or parenterally, can be considered not causing severe DILI.
DILI for compounds administered at medium oral doses (∼10–100
mg daily; 22.2% of drugs under consideration) can be considered unpredictable
because reasonable SAR models were not obtained due to the small size
and heterogeneity of the corresponding dataset. The DILI potential
of the compounds recommended to be used at high oral doses (more than
∼100 mg daily) can be estimated using SAR modeling. The balanced
accuracy of the approach calculated by a 10-fold cross-validation
procedure is 0.803. The developed approach can be used to estimate
severe DILI for druglike compounds proposed to use at low and high
oral doses or parenterally at the early stages of drug development.