Application of Microphysiological Systems to Enhance Safety Assessment in Drug Discovery

Ewart, Lorna; Dehne, Eva-Maria; Fabre, Kristin; Gibbs, Susan; Hickman, James J.; Hornberg, Ellinor; Ingelman‐Sundberg, Magnus; Jang, Kyung Jin; Jones, David R.; Lauschke, Volker M.; Marx, Uwe; Mettetal, Jerome; Pointon, Amy; Williams, Dominic P.; Zimmermann, Wolfram‐Hubertus; Newham, Peter

doi:10.1146/annurev-pharmtox-010617-052722

Cited by 107 publications

(76 citation statements)

References 123 publications

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“…In this context, a plethora of multiorgan systems have been presented, in which a organotypic hepatic model is integrated with models of other tissues in perfused devices. However, as these applications are outside of the scope of this review, we refer the interested reader to excellent recent reviews on this matter …”

Section: D Culture Paradigms For Phhmentioning

confidence: 99%

“…For instance, a longitudinal review of AstraZeneca's small‐molecule drug projects from 2005 to 2010 revealed that overall 29% ( n = 11 out of 38 projects) of projects with low confidence in the preclinical safety profile were closed due to safety issues, whereas none of the compounds with high‐quality safety data was terminated due to safety concerns in the clinics ( n = 0 out of 13) . In light of these findings, it is thus not surprising that much research has focused on the development of preclinical model systems that improve the prediction of hepatotoxic liabilities …”

Section: Applications Of Advanced Primary Human Hepatocyte Culture Momentioning

confidence: 99%

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3D Primary Hepatocyte Culture Systems for Analyses of Liver Diseases, Drug Metabolism, and Toxicity: Emerging Culture Paradigms and Applications

Lauschke

Shafagh

Hendriks

et al. 2019

Biotechnology Journal

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109

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Recent research has shown that the maintenance of relevant liver functions ex vivo requires models in which the cells exhibit an in vivo‐like phenotype, often achieved by reconstitution of appropriate cellular interactions. Multiple different models have been presented that differ in the cells utilized, media, and culture conditions. Furthermore, several technologically different approaches have been presented including bioreactors, chips, and plate‐based systems in fluidic or static media constituting of chemically diverse materials. Using such models, the ability to predict drug metabolism, drug toxicity, and liver functionality have increased tremendously as compared to conventional in vitro models in which cells are cultured as 2D monolayers. Here, the authors highlight important considerations for microphysiological systems for primary hepatocyte culture, review current culture paradigms, and discuss their opportunities for studies of drug metabolism, hepatotoxicity, liver biology, and disease.

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Section: D Culture Paradigms For Phhmentioning

confidence: 99%

Section: Applications Of Advanced Primary Human Hepatocyte Culture Momentioning

confidence: 99%

3D Primary Hepatocyte Culture Systems for Analyses of Liver Diseases, Drug Metabolism, and Toxicity: Emerging Culture Paradigms and Applications

Lauschke

Shafagh

Hendriks

et al. 2019

Biotechnology Journal

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109

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“…Hence, external maturation factors must be applied with great caution when differentiating human pluripotent stem cells . The choice of common medium that balances the critical media component of each organ model is yet to be found . Small number of cells and analyte volume of organoids may hinder analyte detection, thus more sensitive biosensors are needed .…”

Section: Cardiac Organoids Outlookmentioning

confidence: 99%

“…36 The choice of common medium that balances the critical media component of each organ model is yet to be found. 2 Small number of cells and analyte volume of organoids may hinder analyte detection, thus more sensitive biosensors are needed. 2 Furthermore, organoid production reproducibility in terms of size, shape, architecture, cellular composition, and production scalability must be taken into account as additional important factors.…”

Section: Cardiac Organoids Outlookmentioning

confidence: 99%

Human Cardiac Organoids for Disease Modeling

Nugraha

Buono

Boehmer

et al. 2018

Clin Pharma and Therapeutics

121

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Human cardiac drug discovery and disease modeling face challenges in recapitulating cellular complexity and animal‐to‐human translation due to the limitations of conventional 2D cell culture and animal models. The development of human cardiac organoid technologies could help in stimulating and maintaining differentiated cell functions for extended periods of time. By closely mimicking in vivo organ functions in vitro they could thereby help in overcoming the obstacles mentioned above. Through the construction of human cardiac organoids from pluripotent stem cell–derived cells, derived from patients with specific known genotypes and phenotypes, more complex and robust in vitro tools have recently become available for disease modeling. In this review, we will describe the relevance and importance of evolving organoid platforms in disease biology. We further provide examples of cardiac organoid platforms, which may lead the way toward future personalized medicine and drug discovery.

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“…Such microphysiological systems can create Organs-on-Chips and provide novel ways to assess pharmacokinetics, pharmacodynamics, and drug-drug and drug-toxicant interactions. Progress in the creation, validation, and utilization of such systems is reviewed in the articles by Prantil-Baun et al (6) and Ewart et al (7).…”

mentioning

confidence: 99%

Introduction to the Theme “New Approaches for Studying Drug and Toxicant Action: Applications to Drug Discovery and Development”

Insel

Amara

Blaschke

et al. 2018

Annu. Rev. Pharmacol. Toxicol.

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The theme "New Approaches for Studying Drug and Toxicant Action: Applications to Drug Discovery and Development" links 13 articles in this volume of the Annual Review of Pharmacology and Toxicology (ARPT ). The engaging prefatory articles by Arthur Cho and Robert Lefkowitz set the stage for this theme and for the reviews that insightfully describe new approaches that advance research and discovery in pharmacology and toxicology. Examples include the progress being made in developing Organson-Chips/microphysiological systems and human induced pluripotent stem cell-derived cells to aid in understanding cell and tissue pharmacokinetics, action, and toxicity; the recognition of the importance of circadian rhythm, the microbiome, and epigenetics in drug and toxicant responses; and the application of results from new types of patient-derived information to create personalized/precision medicine, including therapeutics for pain, which may perhaps provide help in dealing with the opioid epidemic in the United States. Such new information energizes discovery efforts in pharmacology and toxicology that seek to improve the efficacy and safety of drugs in patients and to minimize the consequences of exposure to toxins. Applications to Drug Discovery and Development," complements and extends the themes of previous volumes ("Precision Medicine and Prediction in Pharmacology" and "New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology"). We believe that this theme will inform readers of findings that have and will continue to have an important impact on pharmacology and toxicology. Below, we highlight 13 articles for the current theme. The highly engaging prefatory articles by Arthur Cho (the previous Editor of ARPT; 1) and Robert Lefkowitz (2) demonstrate their originality in approaching scientific discovery, although in the case of Lefkowitz, this occurred in a rather serendipitous manner. His contributions have been widely recognized, including by the 2012 Nobel Prize in Chemistry. Of note, Lefkowitz's early contributions derive from the use of radioligand binding to identify adrenergic receptors, studies that complement the early work of Solomon Snyder, whose prefatory article appeared in Volume 57 of ARPT (3). Almost 50 years after being introduced and validated as a technique, radioligand binding remains useful for characterizing drug and hormone receptors and defining aspects of receptor biology, including the identification of allosteric modulators, an active area of research and discovery in academia and the drug industry (4, 5).Radioligand binding is a reductionist approach that complements assessments of drug and toxicant responses in physiologic systems, such as organ baths. Recent progress in efforts to create ex vivo models of tissues and organs have involved the use of tissue-derived cells and cell lines that can be assembled in a manner that mimics the in vivo setting. Such microphysiological systems can create Organs-on-Chips and provide novel ways to assess pharmacokinetics, pharm...

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Application of Microphysiological Systems to Enhance Safety Assessment in Drug Discovery

Cited by 107 publications

References 123 publications

3D Primary Hepatocyte Culture Systems for Analyses of Liver Diseases, Drug Metabolism, and Toxicity: Emerging Culture Paradigms and Applications

3D Primary Hepatocyte Culture Systems for Analyses of Liver Diseases, Drug Metabolism, and Toxicity: Emerging Culture Paradigms and Applications

Human Cardiac Organoids for Disease Modeling

Introduction to the Theme “New Approaches for Studying Drug and Toxicant Action: Applications to Drug Discovery and Development”

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