Managing the challenge of drug-induced liver injury: a roadmap for the development and deployment of preclinical predictive models

Weaver, Richard J.; Blomme, Eric A.G.; Chadwick, Amy E.; Copple, Ian M.; Gerets, Helga; Goldring, Christopher E.; Guillouzo, André; Hewitt, Philip; Ingelman‐Sundberg, Magnus; Jensen, Klaus Gjervig; Juhila, Satu; Klingmüller, Ursula; Labbe, Gilles; Liguori, Michael J.; Lovatt, Cerys A.; Morgan, Paul; Naisbitt, Dean J.; Pieters, Raymond; Snoeys, Jan; Water, Bob van de; Williams, Dominic P.; Park, B Kevin

doi:10.1038/s41573-019-0048-x

Cited by 165 publications

(160 citation statements)

References 211 publications

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“…A number of in vitro approaches have been discussed in recent literature [60,[194][195][196][197][198][199][200]. Different companies have varying approaches to predicting toxicity, although many of the main elements are similar.…”

Section: On-going Issuesmentioning

confidence: 99%

A history of the roles of cytochrome P450 enzymes in the toxicity of drugs

Guengerich

2020

Toxicol Res.

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The history of drug metabolism began in the 19th Century and developed slowly. In the mid-20th Century the relationship between drug metabolism and toxicity became appreciated, and the roles of cytochrome P450 (P450) enzymes began to be defined in the 1960s. Today we understand much about the metabolism of drugs and many aspects of safety assessment in the context of a relatively small number of human P450s. P450s affect drug toxicity mainly by either reducing exposure to the parent molecule or, in some cases, by converting the drug into a toxic entity. Some of the factors involved are enzyme induction, enzyme inhibition (both reversible and irreversible), and pharmacogenetics. Issues related to drug toxicity include drug-drug interactions, drug-food interactions, and the roles of chemical moieties of drug candidates in drug discovery and development. The maturation of the field of P450 and drug toxicity has been facilitated by advances in analytical chemistry, computational capability, biochemistry and enzymology, and molecular and cell biology. Problems still arise with P450s and drug toxicity in drug discovery and development, and in the pharmaceutical industry the interaction of scientists in medicinal chemistry, drug metabolism, and safety assessment is critical for success.

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Section: On-going Issuesmentioning

confidence: 99%

A history of the roles of cytochrome P450 enzymes in the toxicity of drugs

Guengerich

2020

Toxicol Res.

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“…Toxicity mechanisms in the liver can involve hepatocyte mitochondrial dysfunction, abnormal transporter activity, abnormal formation of lysosomes, formation of reactive oxygen species, damage of endoplasmic reticulum, and immune-induced injury or damage of nonparenchymal cells that support liver function. 20,128 Similar publications also review the mechanistic causes of cardiotoxicity. [129][130][131][132][133] Cardiotoxicity can lead to the dysfunction of cardiomyocyte physiological mechanisms via drug effects that directly target cardiomyocytes or indirectly affect the function of other cell types that regulate cardiomyocyte function.…”

Section: Toxicitymentioning

confidence: 97%

“…122,123 In addition, both 3D cardiac or hepatic systems can more robustly predict toxicity mechanisms that rely on prolonged drug exposures as their function systematically lasts longer and is more stable than cells in 2D platforms. 41,108,[124][125][126][127] As contexts of use relate to biological mechanisms, Weaver et al 20 proposed a roadmap for implementing preclinical models of hepatotoxicity in which different mechanisms of drug-induced liver injury are comprehensively reviewed. Toxicity mechanisms in the liver can involve hepatocyte mitochondrial dysfunction, abnormal transporter activity, abnormal formation of lysosomes, formation of reactive oxygen species, damage of endoplasmic reticulum, and immune-induced injury or damage of nonparenchymal cells that support liver function.…”

Section: Toxicitymentioning

confidence: 99%

Microengineered systems with iPSC-derived cardiac and hepatic cells to evaluate drug adverse effects

Dame

Ribeiro

2020

Exp Biol Med (Maywood)

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Hepatic and cardiac drug adverse effects are among the leading causes of attrition in drug development programs, in part due to predictive failures of current animal or in vitro models. Hepatocytes and cardiomyocytes differentiated from human induced pluripotent stem cells (iPSCs) hold promise for predicting clinical drug effects, given their human-specific properties and their ability to harbor genetically determined characteristics that underlie inter-individual variations in drug response. Currently, the fetal-like properties and heterogeneity of hepatocytes and cardiomyocytes differentiated from iPSCs make them physiologically different from their counterparts isolated from primary tissues and limit their use for predicting clinical drug effects. To address this hurdle, there have been ongoing advances in differentiation and maturation protocols to improve the quality and use of iPSC-differentiated lineages. Among these are in vitro hepatic and cardiac cellular microsystems that can further enhance the physiology of cultured cells, can be used to better predict drug adverse effects, and investigate drug metabolism, pharmacokinetics, and pharmacodynamics to facilitate successful drug development. In this article, we discuss how cellular microsystems can establish microenvironments for these applications and propose how they could be used for potentially controlling the differentiation of hepatocytes or cardiomyocytes. The physiological relevance of cells is enhanced in cellular microsystems by simulating properties of tissue microenvironments, such as structural dimensionality, media flow, microfluidic control of media composition, and co-cultures with interacting cell types. Recent studies demonstrated that these properties also affect iPSC differentiations and we further elaborate on how they could control differentiation efficiency in microengineered devices. In summary, we describe recent advances in the field of cellular microsystems that can control the differentiation and maturation of hepatocytes and cardiomyocytes for drug evaluation. We also propose how future research with iPSCs within engineered microenvironments could enable their differentiation for scalable evaluations of drug effects. Impact statement Cardiac and hepatic adverse drug effects are among the leading causes of attrition in preclinical and clinical drug development programs as well as marketing withdrawals. The insufficiency of animal testing models has led to considerable interest in the employment of cardiac and hepatic models using human-induced pluripotent stem cells (iPSCs) for drug toxicity testing. However, current batches of iPSC-derived cardiomyocytes and hepatocytes are variable and not matured as adult primary tissues, which limit their prediction of drug effects. This article discusses how the use of microfluidics can create microenvironments to better control differentiation protocols and increase the physiological relevance of iPSC-derived cardiomyocytes and hepatocytes. Development and standardization of technologies will enable evaluation of the potential value of cellular microsystems to improve the in vitro models used in drug development programs. Future steps in this field include controlled connections of organ systems to better recreate clinical metabolism and pharmacokinetics.

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“…This indicates that the technology offered is still in development and not in its final form: only in the last couple of years, the emerging OOAC companies have established partnerships and collaborative relationships with pharmaceutical companies to accelerate the development of OOAC technology and testing [27]. Peer-reviewed publications of analytical results from these operational environments have reported the first successful applications in operational conditions (TRL 7) and confirmed the potential for OOAC to improve the process for predictions of adverse drug reactions before drug candidates enter clinical trials [131,132].…”

Section: Trlmentioning

confidence: 99%

Translational Roadmap for the Organs-on-a-Chip Industry toward Broad Adoption

et al. 2020

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Organs-on-a-Chip (OOAC) is a disruptive technology with widely recognized potential to change the efficiency, effectiveness, and costs of the drug discovery process; to advance insights into human biology; to enable clinical research where human trials are not feasible. However, further development is needed for the successful adoption and acceptance of this technology. Areas for improvement include technological maturity, more robust validation of translational and predictive in vivo-like biology, and requirements of tighter quality standards for commercial viability. In this review, we reported on the consensus around existing challenges and necessary performance benchmarks that are required toward the broader adoption of OOACs in the next five years, and we defined a potential roadmap for future translational development of OOAC technology. We provided a clear snapshot of the current developmental stage of OOAC commercialization, including existing platforms, ancillary technologies, and tools required for the use of OOAC devices, and analyze their technology readiness levels. Using data gathered from OOAC developers and end-users, we identified prevalent challenges faced by the community, strategic trends and requirements driving OOAC technology development, and existing technological bottlenecks that could be outsourced or leveraged by active collaborations with academia.

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Managing the challenge of drug-induced liver injury: a roadmap for the development and deployment of preclinical predictive models

Cited by 165 publications

References 211 publications

A history of the roles of cytochrome P450 enzymes in the toxicity of drugs

A history of the roles of cytochrome P450 enzymes in the toxicity of drugs

Microengineered systems with iPSC-derived cardiac and hepatic cells to evaluate drug adverse effects

Translational Roadmap for the Organs-on-a-Chip Industry toward Broad Adoption

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