Translating Clinical Findings into Knowledge in Drug Safety Evaluation - Drug Induced Liver Injury Prediction System (DILIps)

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60–70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the “Rule of Three” was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity. Author Summary: Translational research involves utilization of clinical data to address challenges in drug discovery and development. The rationale behind this study is that the side effects observed in clinical trial and post-marketing surveillance can be translated into a screening system for use in drug discovery. As a proof-of-concept study, we developed an in silico system based on 13 hepatotoxic side effects to predict drug-induced liver injury (DILI), which is one of the most frequent causes of drug failure in clinical trial and withdrawal from post-marketing application, and also one of the most difficult clinical endpoints to predict from preclinical studies. We first identified 13 types of liver injury which yielded high prediction accuracy to distinguish drugs known to cause DILI from these don't. To effectively apply these 13 hepatotoxic side effects to the drug discovery process for DILI, we developed in silico models for each of these side effects solely based on chemical structure data. Finally, we constructed a DILI prediction system (DILIps) by combining these 13 in silico models in a consensus fashion, which yielded >91% positive predictive value for DILI in humans. The DILIps methodology can be extended in applications for addressing other drug safety issues, such as renal and cardiovascular toxicity.