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

Abstract

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.