Optimizing drug discovery by Investigative Toxicology: Current and future trends

Beilmann, Mario

doi:10.14573/altex.1808181

Cited by 37 publications

(33 citation statements)

References 184 publications

(210 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…More examples of safety assessments, especially for high-risk exposures and a variety of MoAs are needed to test whether the panels used are protective. The final area of uncertainty that warrants additional work is the extrapolation of PoDs from static, short-term in vitro systems to longer term systems able to mimic in vivo exposures ( Beilmann et al , 2019 ; Ewart et al , 2018 ).…”

Section: Discussionmentioning

confidence: 99%

A Next-Generation Risk Assessment Case Study for Coumarin in Cosmetic Products

Baltazar

Cable

Carmichael

et al. 2020

Toxicological Sciences

106

View full text Add to dashboard Cite

Abstract Next-Generation Risk Assessment is defined as an exposure-led, hypothesis-driven risk assessment approach that integrates new approach methodologies (NAMs) to assure safety without the use of animal testing. These principles were applied to a hypothetical safety assessment of 0.1% coumarin in face cream and body lotion. For the purpose of evaluating the use of NAMs, existing animal and human data on coumarin were excluded. Internal concentrations (plasma Cmax) were estimated using a physiologically based kinetic model for dermally applied coumarin. Systemic toxicity was assessed using a battery of in vitro NAMs to identify points of departure (PoDs) for a variety of biological effects such as receptor-mediated and immunomodulatory effects (Eurofins SafetyScreen44 and BioMap Diversity 8 Panel, respectively), and general bioactivity (ToxCast data, an in vitro cell stress panel and high-throughput transcriptomics). In addition, in silico alerts for genotoxicity were followed up with the ToxTracker tool. The PoDs from the in vitro assays were plotted against the calculated in vivo exposure to calculate a margin of safety with associated uncertainty. The predicted Cmax values for face cream and body lotion were lower than all PoDs with margin of safety higher than 100. Furthermore, coumarin was not genotoxic, did not bind to any of the 44 receptors tested and did not show any immunomodulatory effects at consumer-relevant exposures. In conclusion, this case study demonstrated the value of integrating exposure science, computational modeling and in vitro bioactivity data, to reach a safety decision without animal data.

show abstract

Section: Discussionmentioning

confidence: 99%

A Next-Generation Risk Assessment Case Study for Coumarin in Cosmetic Products

Baltazar

Cable

Carmichael

et al. 2020

Toxicological Sciences

106

View full text Add to dashboard Cite

show abstract

“…Already some CSs in partnership with external industry stakeholders were initiated. Such joint CSs help to (1) inform strategic decisions, (2) prioritize chemicals within a group, and (3) support the problem-solving process in investigative toxicology (Beilmann et al 2019 ). Furthermore, the sustainability of the approaches will be supported by a commercialization platform that consolidates NAMs and NAM data from different partner organizations, and use the integrated results in both safety assessment and investigative toxicology.…”

Section: Gaps and Future Requirementsmentioning

confidence: 99%

Setting the stage for next-generation risk assessment with non-animal approaches: the EU-ToxRisk project experience

et al. 2020

View full text Add to dashboard Cite

In 2016, the European Commission launched the EU-ToxRisk research project to develop and promote animal-free approaches in toxicology. The 36 partners of this consortium used in vitro and in silico methods in the context of case studies (CSs). These CSs included both compounds with a highly defined target (e.g. mitochondrial respiratory chain inhibitors) as well as compounds with poorly defined molecular initiation events (e.g. short-chain branched carboxylic acids). The initial project focus was on developing a science-based strategy for read-across (RAx) as an animal-free approach in chemical risk assessment. Moreover, seamless incorporation of new approach method (NAM) data into this process (= NAM-enhanced RAx) was explored. Here, the EU-ToxRisk consortium has collated its scientific and regulatory learnings from this particular project objective. For all CSs, a mechanistic hypothesis (in the form of an adverse outcome pathway) guided the safety evaluation. ADME data were generated from NAMs and used for comprehensive physiological-based kinetic modelling. Quality assurance and data management were optimized in parallel. Scientific and Regulatory Advisory Boards played a vital role in assessing the practical applicability of the new approaches. In a next step, external stakeholders evaluated the usefulness of NAMs in the context of RAx CSs for regulatory acceptance. For instance, the CSs were included in the OECD CS portfolio for the Integrated Approach to Testing and Assessment project. Feedback from regulators and other stakeholders was collected at several stages. Future chemical safety science projects can draw from this experience to implement systems toxicology-guided, animal-free next-generation risk assessment.

show abstract

“…Platforms that have sufficient scale and reproducibility to generate large reference databases are particularly useful as they provide a relational connection between targets and clinical outcomes. Anchoring phenotypic NAMs to a mechanistic framework such as those provided by the AOP construct will help with adoption of these approaches, as toxicology moves away from a descriptive science to an evidence-based, mechanistic discipline (Beilmann et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…The use of "omics" profiling technologies (genomics, proteomics, metabolomics, etc. ) and in vitro methods in discovery toxicology has exploded in recent years and begun to advance our understanding of toxicity mechanisms (Beilmann et al, 2019;Thomas et al, 2019). The field is still young, however, as the molecular mechanisms underlying most human toxicities remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Human Cell-Based in vitro Phenotypic Profiling for Drug Safety-Related Attrition

Berg

2019

Front. Big Data

View full text Add to dashboard Cite

Ensuring the safety of new drugs is critically important to regulators, pharmaceutical researchers and patients alike. Even so, unexpected toxicities still account for 20-30% of clinical trial failures, in part due to the persistence of animal testing as the primary approach for de-risking new drugs. Clearly, improved methods for safety attrition that incorporate human-relevant biology are needed. This recognition has spurred interest in non-animal alternatives or new approach methodologies (NAMs) including in vitro models that utilize advances in the culture of human cell types to provide greater clinical relevance for assessing risk. These phenotypic assay systems use human primary and induced pluripotent stem cell-derived cells in various formats, including co-cultures and advanced cellular systems such as organoids, bioprinted tissues, and organs-on-a-chip. Despite the promise of these human-based phenotypic approaches, adoption of these platforms into drug discovery programs for reducing safety-related attrition has been slow. Here we discuss the value of large-scale human cell-based phenotypic profiling for incorporating human-specific biology into the de-risking process. We describe learnings from our experiences with human primary cell-based assays and analysis of clinically relevant reference datasets in developing in vitro-based toxicity signatures. We also describe how Adverse Outcome Pathway (AOP) frameworks can be used to integrate results from diverse platforms congruent with weight-of-evidence approaches from risk assessment to improve safety-related decisions in early discovery.

show abstract

Optimizing drug discovery by Investigative Toxicology: Current and future trends

Cited by 37 publications

References 184 publications

A Next-Generation Risk Assessment Case Study for Coumarin in Cosmetic Products

A Next-Generation Risk Assessment Case Study for Coumarin in Cosmetic Products

Setting the stage for next-generation risk assessment with non-animal approaches: the EU-ToxRisk project experience

Human Cell-Based in vitro Phenotypic Profiling for Drug Safety-Related Attrition

Contact Info

Product

Resources

About