Most Influential Physicochemical and in Vitro Assay Descriptors for Hepatotoxicity and Nephrotoxicity Prediction
Drug-induced organ injury is a major reason for drug candidate attrition in preclinical and clinical drug development. The liver, kidneys, and heart have been recognized as the most common organ systems affected in safety-related attrition or the subject of black box warnings and postmarket drug withdrawals. In silico physicochemical property calculations and in vitro assays have been utilized separately in the early stages of the drug discovery and development process to predict drug safety. In this study, we combined physicochemical properties and in vitro cytotoxicity assays including mitochondrial dysfunction to build organ-specific univariate and multivariable logistic regression models to achieve odds ratios for the prediction of clinical hepatotoxicity, nephrotoxicity, and cardiotoxicity using 215 marketed drugs. The multivariable hepatotoxic predictive model showed an odds ratio of 6.2 (95% confidence interval (CI) 1.7-22.8) or 7.5 (95% CI 3.2-17.8) for mitochondrial inhibition or drug plasma Cmax >1 μM for drugs associated with liver injury, respectively. The multivariable nephrotoxicity predictive model showed an odds ratio of 5.8 (95% CI 2.0-16.9), 6.4 (95% CI 1.1-39.3), or 15.9 (95% CI 2.8-89.0) for drug plasma Cmax >1 μM, mitochondrial inhibition, or hydrogen-bond-acceptor atoms >7 for drugs associated with kidney injury, respectively. Conversely, drugs with a total polar surface area ≥75 Å were 79% (odds ratio 0.21, 95% CI 0.061-0.74) less likely to be associated with kidney injury. Drugs belonging to the extended clearance classification system (ECCS) class 4, where renal secretion is the primary clearance mechanism (low permeability drugs that are bases/neutrals), were 4 (95% CI 1.8-9.5) times more likely to to be associated with kidney injury with this data set. Alternatively, ECCS class 2 drugs, where hepatic metabolism is the primary clearance (high permeability drugs that are bases/neutrals) were 77% less likely (odds ratio 0.23 95% CI 0.095-0.54) to to be associated with kidney injury. A cardiotoxicity model was poorly defined using any of these drug physicochemical attributes. Combining in silico physicochemical properties descriptors along with in vitro toxicity assays can be used to build predictive toxicity models to select small molecule therapeutics with less potential to cause liver and kidney organ toxicity.