Evolution of Experimental Models of the Liver to Predict Human Drug Hepatotoxicity and Efficacy

Vernetti, Lawrence; Vogt, Andreas; Gough, Albert; Taylor, D. Lansing

doi:10.1016/j.cld.2016.08.013

Cited by 39 publications

(28 citation statements)

References 64 publications

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“…The 3D cell culture systems may more accurately reflect the physiology of the organ and has recently resulted in development of several static and perfused organotypic models. Recent reviews in the field have excellently summarized the novel models such as organ‐hollow fibre 3D bioreactors, organ on‐a‐chip platforms including micropatterned cocultures, perfused multiwell plates and microfluidic liver biochips . The recent publication by Bell and coworkers show that primary human hepatocytes cultured in spheroids retain a proteome profile very similar to the liver tissue it was isolated from.…”

Section: In Vitro Models To Study Drug Metabolism and Drug‐induced LImentioning

confidence: 99%

Evolution of Novel 3D Culture Systems for Studies of Human Liver Function and Assessments of the Hepatotoxicity of Drugs and Drug Candidates

Andersson

2017

Basic Clin Pharma Tox

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The pharmaceutical industry urgently needs reliable pre-clinical models to evaluate the efficacy and safety of new chemical entities before they enter the clinical trials. Development of in vitro model systems that emulate the functions of the human liver organ has been an elusive task. Cell lines exhibit a low drug-metabolizing capacity and primary liver cells rapidly dedifferentiate in culture, which restrict their usefulness substantially. Recently, the development of hepatocyte spheroid cultures has shown promising results. The proteome and transcriptome in the spheroids were similar to the liver tissue, and hepatotoxicity of selected substances was detected at in vivo-relevant concentrations. The Drug Discovery DilemmaThe drug discovery process is suffering from poor productivity as depicted by the low number of new chemical entities that survives the clinical drug development phases. The termination of compounds in late pre-clinical and early clinical phases is mainly due to safety and poor efficacy [1,2]. The lessons learned from the AstraZeneca pipeline are that 82% of projects that are closed during the pre-clinical phase is due to unacceptable safety profile. In the clinical phases I and II, the closure of projects due to efficacy is increasing and in Phase IIb, and the number is as high as 88% of all projects that were terminated at this stage [1]. The poor translation of animal to human being is illustrated by the fact that animal testing identified only 70% of compounds that are toxic in human beings [3]. Another interesting finding is that 37% of first in class drugs discovered between 1999 and 2008 was based mainly on phenotypic pre-clinical screening (animal or in vitro models where a pharmacological response is measured but the target is not known), while only 23% of the first in class drugs was based on target-based screening [4]. This is in an era where the majority of the drug discovery is focused on target-based screening. Target-based screening is easily set up in a highthroughput format, and thus, a large number of substances can be screened. High-throughput format usually also delivers very potent and selective substances for the specific target nominated. However, the poor clinical outcome clearly indicates that the pre-clinical animal and in vitro models that are used to select efficacious and safe compounds do not translate into the human being.

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Section: In Vitro Models To Study Drug Metabolism and Drug‐induced LImentioning

confidence: 99%

Evolution of Novel 3D Culture Systems for Studies of Human Liver Function and Assessments of the Hepatotoxicity of Drugs and Drug Candidates

Andersson

2017

Basic Clin Pharma Tox

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“…In vitro models are also increasingly leveraging advances in tissue engineering, microfluidics, and real-time biosensors of physiological processes. These in vitro models range in the extent to which they mimic in vivo conditions from relatively simple spheroids (51), through patient tissue-derived organoids, self-organizing stemcell-based organoids (51,52), single "organs on chips" (OoC) under flow, and integrated, multi-OoC microphysiology systems (MPS) (53)(54)(55)(56)(57)(58)(59). While still relatively high-throughput, these models from both healthy and diseased tissues have greater similarity to the chemistry, threedimensional structure and component localization, environment, and possibly genetic stability of an intact organism than classical cell cultures grown on relatively flat substrates.…”

Section: In Vitro Modelsmentioning

confidence: 99%

Improving Natural Product Research Translation: from Source to Clinical Trial

Sorkin¹,

Kuszak²,

Fukagawa³

et al. 2019

Preprint

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While great interest in health effects of natural product (NP) including dietary supplements and foods persists, promising preclinical NP research is not consistently translating into actionable clinical trial (CT) outcomes. Generally considered the gold standard for assessing safety and efficacy, CTs, especially phase III CTs, are costly and require rigorous planning to optimize the value of the information obtained. More effective bridging from NP research to CT was the goal of a https://events-support.com/events/Natural_Product_Clinical_Trials. Participants emphasized that replicability and likelihood of successful translation depend on rigor in experimental design, interpretation, and reporting across the continuum of NP research. Discussions spanned good practices for NP characterization and quality control; use and interpretation of models (computational through in vivo) with strong clinical predictive validity; controls for experimental artefacts, especially for in vitro interrogation of bioactivity and mechanisms of action; rigorous assessment and interpretation of prior research; transparency in all reporting; and prioritization of research questions. Natural product clinical trials prioritized based on rigorous, convergent supporting data and current public health needs are most likely to be informative and ultimately affect public health. Thoughtful, coordinated implementation of these practices should enhance the knowledge gained from future NP research.

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“…of simple and complex 2D in vitro assays can predict up to 80% of human hepatotoxicity (Noor et al, 2009;Vernetti et al, 2017).…”

Section: Limitations Of Animal Models In Liver Toxicity Evaluationsmentioning

confidence: 99%

“…This new developing area, currently also referred to as quantitative systems pharmacology, focuses on the drugability of targets in biological systems. Quantitative systems pharmacology, in fact, follows a systems biology approach to drug discovery, aimed at the underlying mechanisms of drug actions on multiscale systems, using iterative computational modeling (Knight-Schrijver et al, 2016;Vernetti et al, 2017).…”

Section: Computational In Silico Toolsmentioning

confidence: 99%

“…The in vivo relevance of these systems will have to be validated. Advanced microfluidic systems, in future, will include liver zonation (Vernetti et al, 2017). The application of hiPSC-derived models in human disease research, in future, will move in vitro systems from mostly proliferating cell lines towards patient-specific cells and will, thus, facilitate personalized systems medicine.…”

Section: Toxicology In the Coming Years: Challenges And Perspectivesmentioning

confidence: 99%

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The Changing Paradigm in Preclinical Toxicology: in vitro and in silico Methods in Liver Toxicity Evaluations

Noor¹

2019

Animal Experimentation: Working Towards a Paradigm Change

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Evolution of Experimental Models of the Liver to Predict Human Drug Hepatotoxicity and Efficacy

Cited by 39 publications

References 64 publications

Evolution of Novel 3D Culture Systems for Studies of Human Liver Function and Assessments of the Hepatotoxicity of Drugs and Drug Candidates

Evolution of Novel 3D Culture Systems for Studies of Human Liver Function and Assessments of the Hepatotoxicity of Drugs and Drug Candidates

Improving Natural Product Research Translation: from Source to Clinical Trial

The Changing Paradigm in Preclinical Toxicology: in vitro and in silico Methods in Liver Toxicity Evaluations

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