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Stem cells, organoids and microphysiological systems coupled to modeling & simulation guide drug discovery and enhance translational safety risk assessment
Toxicology Letters 280S (2017) S78–S79
Contents lists available at ScienceDirect
Toxicology Letters journal homepage: www.elsevier.com/locate/toxlet
The investigative toxicology consortium symposium – Part 2
ISS 1b-01 Stem cells, organoids and microphysiological systems coupled to modeling & simulation guide drug discovery and enhance translational safety risk assessment
ISS 1b-02 Case study: Identification of off/on target mechanisms effects inducing genotoxicty
Pete Newham
Preclinical Safety - Global Operation Germany, Sanofi, Frankfurt, Germany
Andreas Czich
Drug Safety & Metabolism, AstraZeneca, Cambridge, United Kingdom 3D human cell culture models and “organoid” models, can recapitulate tissue biology at a more physiological level compared to conventionally used 2D static cell cultures; enabling improved biological understanding of candidate drugs and their potential for toxicity. In addition, more quantitative safety risk assessments can be achieved when in vitro data is coupled to pharmacokinetic/pharmacodynamic (PK/PD) or systems pharmacology models, which allow translation of time-course and magnitude across biological systems, accounting for differences between in vitro and in vivo physiology. Here we explore the use of organoid and stem cell models to provide translational safety risk assessment of oncology drug candidates. In the first case study we utilise cross-species gastrointestinal organoids to determine on target liabilities and human risk assessment, while in the second example, we utilise cell-cycle data along with a mathematical model of haematopoietic cell production, effectively combining in vitro and in vivo data to provide quantified risk assessment of bone marrow toxicity in cancer patient populations. Finally, we consider the recent advancement of microfluidic organ-on-achip systems, which provide an opportunity to further enhance the physiologically relevant aspects of organ function on a human microphysiological scale in the form of a dynamic bone marrow model, which when coupled with systems pharmacology models has the potential to minimize animal studies and effectively guide clinical use of candidate drug. http://dx.doi.org/10.1016/j.toxlet.2017.07.206
In vitro genotoxicity testing is part of the regulatory testing strategy. Screening assays are well established to predict the outcome of the regulatory assays. However, the new targets under investigation are often complex impacting several cellular pathways. To perform a thorough risk assessment and get a mechanistic understanding, mechanistic studies are applied to identify potential mechanisms of the observed genotoxicity. Results from those studies are supportive for threshold discussions of this effect. In the research environment, the understanding of the genotoxic effects are supporting the optimization and selection of Lead structures in the research environment. For this understanding, a throrough target assessment including a pathway analysis as important as a strong interaction between in silico methods and the in vitro models. This is an continuous feedback and learning process that is applied to mitigate the risk of a new drug candidates http://dx.doi.org/10.1016/j.toxlet.2017.07.207 ISS 1b-03 Case study: Addressing human relevance preclinical tumor findings using advanced cell models Adrian Roth Pharmaceutical Sciences, Roche Innovation Centre Basel, Hoffmann-La Roche Ltd, Basel, Switzerland Drug induced neoplastic changes are a frequent phenomenon in pre-clinical safety studies, in particular in rodents exposed over longer time. While for some of these effects considerable clinical evidence suggests that they do not translate to humans, de-risking packages delineating a mode of action and data demonstrating rodent-specificity is generally warranted by regulatory authorities. By use of primary, stem cell or patient-derived 3D cell models from rodent and human, mechanistic in vitro packages can be generated providing supporting evidence for known non-human relevant pathways involved such as nuclear receptor-driven liver
0378-4274/
Contents lists available at ScienceDirect
Toxicology Letters journal homepage: www.elsevier.com/locate/toxlet
The investigative toxicology consortium symposium – Part 2
ISS 1b-01 Stem cells, organoids and microphysiological systems coupled to modeling & simulation guide drug discovery and enhance translational safety risk assessment
ISS 1b-02 Case study: Identification of off/on target mechanisms effects inducing genotoxicty
Pete Newham
Preclinical Safety - Global Operation Germany, Sanofi, Frankfurt, Germany
Andreas Czich
Drug Safety & Metabolism, AstraZeneca, Cambridge, United Kingdom 3D human cell culture models and “organoid” models, can recapitulate tissue biology at a more physiological level compared to conventionally used 2D static cell cultures; enabling improved biological understanding of candidate drugs and their potential for toxicity. In addition, more quantitative safety risk assessments can be achieved when in vitro data is coupled to pharmacokinetic/pharmacodynamic (PK/PD) or systems pharmacology models, which allow translation of time-course and magnitude across biological systems, accounting for differences between in vitro and in vivo physiology. Here we explore the use of organoid and stem cell models to provide translational safety risk assessment of oncology drug candidates. In the first case study we utilise cross-species gastrointestinal organoids to determine on target liabilities and human risk assessment, while in the second example, we utilise cell-cycle data along with a mathematical model of haematopoietic cell production, effectively combining in vitro and in vivo data to provide quantified risk assessment of bone marrow toxicity in cancer patient populations. Finally, we consider the recent advancement of microfluidic organ-on-achip systems, which provide an opportunity to further enhance the physiologically relevant aspects of organ function on a human microphysiological scale in the form of a dynamic bone marrow model, which when coupled with systems pharmacology models has the potential to minimize animal studies and effectively guide clinical use of candidate drug. http://dx.doi.org/10.1016/j.toxlet.2017.07.206
In vitro genotoxicity testing is part of the regulatory testing strategy. Screening assays are well established to predict the outcome of the regulatory assays. However, the new targets under investigation are often complex impacting several cellular pathways. To perform a thorough risk assessment and get a mechanistic understanding, mechanistic studies are applied to identify potential mechanisms of the observed genotoxicity. Results from those studies are supportive for threshold discussions of this effect. In the research environment, the understanding of the genotoxic effects are supporting the optimization and selection of Lead structures in the research environment. For this understanding, a throrough target assessment including a pathway analysis as important as a strong interaction between in silico methods and the in vitro models. This is an continuous feedback and learning process that is applied to mitigate the risk of a new drug candidates http://dx.doi.org/10.1016/j.toxlet.2017.07.207 ISS 1b-03 Case study: Addressing human relevance preclinical tumor findings using advanced cell models Adrian Roth Pharmaceutical Sciences, Roche Innovation Centre Basel, Hoffmann-La Roche Ltd, Basel, Switzerland Drug induced neoplastic changes are a frequent phenomenon in pre-clinical safety studies, in particular in rodents exposed over longer time. While for some of these effects considerable clinical evidence suggests that they do not translate to humans, de-risking packages delineating a mode of action and data demonstrating rodent-specificity is generally warranted by regulatory authorities. By use of primary, stem cell or patient-derived 3D cell models from rodent and human, mechanistic in vitro packages can be generated providing supporting evidence for known non-human relevant pathways involved such as nuclear receptor-driven liver
0378-4274/