In silico toxicology protocols

The present publication surveys several applications of in silico (i.e., computational) toxicology approaches across different industries and institutions. It highlights the need to develop standardized protocols when conducting toxicity-related predictions. This contribution articulates the information needed for protocols to support in silico predictions for major toxicological endpoints of concern (e.g., genetic toxicity, carcinogenicity, acute toxicity, reproductive toxicity, developmental toxicity) across several industries and regulatory bodies. Such novel in silico toxicology (IST) protocols, when fully developed and implemented, will ensure in silico toxicological assessments are performed and evaluated in a consistent, reproducible, and well-documented manner across industries and regulatory bodies to support wider uptake and acceptance of the approaches. The development of IST protocols is an initiative developed through a collaboration among an international consortium to reflect the state-of-the-art in in silico toxicology for hazard identification and characterization. A general outline for describing the development of such protocols is included and it is based on in silico predictions and/or available experimental data for a defined series of relevant toxicological effects or mechanisms. The publication presents a novel approach for determining the reliability of in silico predictions alongside experimental data. In addition, we discuss how to determine the level of confidence in the assessment based on the relevance and reliability of the information

Toward Quantitative Models in Safety Assessment: A Case Study to Show Impact of Dose–Response Inference on hERG Inhibition Models

Due to challenges with historical data and the diversity of assay formats, in silico models for safety-related endpoints are often based on discretized data instead of the data on a natural continuous scale. Models for discretized endpoints have limitations in usage and interpretation that can impact compound design. Here, we present a consistent data inference approach, exemplified on two data sets of Ether-à-go-go-Related Gene (hERG) K+ inhibition data, for dose–response and screening experiments that are generally applicable for in vitro assays. hERG inhibition has been associated with severe cardiac effects and is one of the more prominent safety targets assessed in drug development, using a wide array of in vitro and in silico screening methods. In this study, the IC50 for hERG inhibition is estimated from diverse historical proprietary data. The IC50 derived from a two-point proprietary screening data set demonstrated high correlation (R = 0.98, MAE = 0.08) with IC50s derived from six-point dose–response curves. Similar IC50 estimation accuracy was obtained on a public thallium flux assay data set (R = 0.90, MAE = 0.2). The IC50 data were used to develop a robust quantitative model. The model’s MAE (0.47) and R2 (0.46) were on par with literature statistics and approached assay reproducibility. Using a continuous model has high value for pharmaceutical projects, as it enables rank ordering of compounds and evaluation of compounds against project-specific inhibition thresholds. This data inference approach can be widely applicable to assays with quantitative readouts and has the potential to impact experimental design and improve model performance, interpretation, and acceptance across many standard safety endpoints

Generalized Workflow for Generating Highly Predictive in Silico Off‑Target Activity Models

Chemical structure data and corresponding measured bioactivities of compounds are nowadays easily available from public and commercial databases. However, these databases contain heterogeneous data from different laboratories determined under different protocols and, in addition, sometimes even erroneous entries. In this study, we evaluated the use of data from bioactivity databases for the generation of high quality in silico models for off-target mediated toxicity as a decision support in early drug discovery and crop-protection research. We chose human acetylcholinesterase (hAChE) inhibition as an exemplary end point for our case study. A standardized and thorough quality management routine for input data consisting of more than 2,200 chemical entities from bioactivity databases was established. This procedure finally enables the development of predictive QSAR models based on heterogeneous in vitro data from multiple laboratories. An extended applicability domain approach was used, and regression results were refined by an error estimation routine. Subsequent classification augmented by special consideration of borderline candidates leads to high accuracies in external validation achieving correct predictive classification of 96%. The standardized process described herein is implemented as a (semi)­automated workflow and thus easily transferable to other off-targets and assay readouts

Generating modeling data from repeat-dose toxicity reports

Over the past decades, pharmaceutical companies have conducted a large number of high-quality in vivo repeat-dose toxicity (RDT) studies for regulatory purposes. As part of the eTOX project, a high number of these studies have been compiled and integrated into a database. This valuable resource can be queried directly, but it can be further exploited to build predictive models. As the studies were originally conducted to investigate the properties of individual compounds, the experimental conditions across the studies are highly heterogeneous. Consequently, the original data required normalization/standardization, filtering, categorization and integration to make possible any data analysis (such as building predictive models). Additionally, the primary objectives of the RDT studies were to identify toxicological findings, most of which do not directly translate to in vivo endpoints. This article describes a method to extract datasets containing comparable toxicological properties for a series of compounds amenable for building predictive models. The proposed strategy starts with the normalization of the terms used within the original reports. Then, comparable datasets are extracted from the database by applying filters based on the experimental conditions. Finally, carefully selected profiles of toxicological findings are mapped to endpoints of interest, generating QSAR-like tables. In this work, we describe in detail the strategy and tools used for carrying out these transformations and illustrate its application in a data sample extracted from the eTOX database. The suitability of the resulting tables for developing hazard-predicting models was investigated by building proof-of-concept models for in vivo liver endpoints.Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115002 (eTOX), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies' in-kind contributions. Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 777365 (eTRANSAFE). This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA companies' in-kind contributions

Towards implementing virtual control groups in nonclinical safety studies: Workshop report and roadmap to implementation

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In silico approaches in organ toxicity hazard assessment: Current status and future needs in predicting liver toxicity

Hepatotoxicity is one of the most frequently observed adverse effects resulting from exposure to a xenobiotic. For example, in pharmaceutical research and development it is one of the major reasons for drug withdrawals, clinical failures, and discontinuation of drug candidates. The development of faster and cheaper methods to assess hepatotoxicity that are both more sustainable and more informative is critically needed. The biological mechanisms and processes underpinning hepatotoxicity are summarized and experimental approaches to support the prediction of hepatotoxicity are described, including toxicokinetic considerations. The paper describes the increasingly important role of in silico approaches and highlights challenges to the adoption of these methods including the lack of a commonly agreed upon protocol for performing such an assessment and the need for in silico solutions that take dose into consideration. A proposed framework for the integration of in silico and experimental information is provided along with a case study describing how computational methods have been used to successfully respond to a regulatory question concerning non-genotoxic impurities in chemically synthesized pharmaceuticals

Generating modeling data from repeat-dose toxicity reports

Over the past decades, pharmaceutical companies have conducted a large number of high-quality in vivo repeat-dose toxicity (RDT) studies for regulatory purposes. As part of the eTOX project, a high number of these studies have been compiled and integrated into a database. This valuable resource can be queried directly, but it can be further exploited to build predictive models. As the studies were originally conducted to investigate the properties of individual compounds, the experimental conditions across the studies are highly heterogeneous. Consequently, the original data required normalization/standardization, filtering, categorization and integration to make possible any data analysis (such as building predictive models). Additionally, the primary objectives of the RDT studies were to identify toxicological findings, most of which do not directly translate to in vivo endpoints. This article describes a method to extract datasets containing comparable toxicological properties for a series of compounds amenable for building predictive models. The proposed strategy starts with the normalization of the terms used within the original reports. Then, comparable datasets are extracted from the database by applying filters based on the experimental conditions. Finally, carefully selected profiles of toxicological findings are mapped to endpoints of interest, generating QSAR-like tables. In this work, we describe in detail the strategy and tools used for carrying out these transformations and illustrate its application in a data sample extracted from the eTOX database. The suitability of the resulting tables for developing hazard-predicting models was investigated by building proof-of-concept models for in vivo liver endpoints.Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115002 (eTOX), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies' in-kind contributions. Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 777365 (eTRANSAFE). This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA companies' in-kind contributions