In vitro to in vivo extrapolation for high throughput prioritization and decision making

Bell, Shannon; Chang, Xiaoqing; Wambaugh, John F.; Allen, David; Bartels, Mike; Brouwer, Kim L. R.; Casey, Warren; Choksi, Neepa; Ferguson, Stephen S. G.; Fraczkiewicz, Grazyna; Jarabek, Annie M.; Ke, Alice Ban; Lumen, Annie; Lynn, Scott G.; Paini, Alicia; Price, Paul S.; Ring, Caroline; Simon, Timothy M.; Sipes, Nisha S.; Sprankle, Catherine S.; Strickland, Judy; Troutman, John; Wetmore, Barbara A.; Kleinstreuer, Nicole

doi:10.1016/j.tiv.2017.11.016

Cited by 186 publications

(140 citation statements)

References 110 publications

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“…Some progress has been achieved in incorporating population pharmacokinetics to address variability in the processes of absorption, distribution, metabolism, and excretion, including use of in silico and in vitro methods (Jamei, 2016). Indeed, population-based in vitro-in vivo extrapolation (IVIVE) to address pharmacokinetic variability is an increasingly common step in safety evaluations for both pharmaceuticals and environmental chemicals (Bell et al, 2017; Wetmore, 2015). However, it is well-recognized that pharmacodynamic processes likely contribute equally, if not more, to inter-individual variability (Turner et al, 2015; Zeise et al, 2013; Hattis and Lynch, 2007).…”

Section: Introductionmentioning

confidence: 99%

A human population-based organotypic in vitro model for cardiotoxicity screening

Grimm

Blanchette

House

et al. 2018

ALTEX

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Assessing inter-individual variability in responses to xenobiotics remains a substantial challenge, both in drug development with respect to pharmaceuticals and in public health with respect to environmental chemicals. Although approaches exist to characterize pharmacokinetic variability, there are no methods to routinely address pharmacodynamic variability. In this study, we aimed to demonstrate the feasibility of characterizing inter-individual variability in a human in vitro model. Specifically, we hypothesized that genetic variability across a population of iPSC-derived cardiomyocytes translates into reproducible variability in both baseline phenotypes and drug responses. We measured baseline and drug-related effects in iPSC-derived cardiomyocytes from 27 healthy donors on kinetic Ca2+ flux and high-content live cell imaging. Cells were treated in concentration-response with cardiotoxic drugs: isoproterenol (β-adrenergic receptor agonist/positive inotrope), propranolol (β-adrenergic receptor antagonist/negative inotrope), and cisapride (hERG channel inhibitor/QT prolongation). Cells from four of the 27 donors were further evaluated in terms of baseline and treatment-related gene expression. Reproducibility of phenotypic responses was evaluated across batches and time. iPSC-derived cardiomyocytes exhibited reproducible donor-specific differences in baseline function and drug-induced effects. We demonstrate the feasibility of using a panel of population-based organotypic cells from healthy donors as an animal replacement experimental model. This model can be used to rapidly screen drugs and chemicals for inter-individual variability in cardiotoxicity. This approach demonstrates the feasibility of quantifying inter-individual variability in xenobiotic responses and can be expanded to other cell types for which in vitro populations can be derived from iPSCs.

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Section: Introductionmentioning

confidence: 99%

A human population-based organotypic in vitro model for cardiotoxicity screening

Grimm

Blanchette

House

et al. 2018

ALTEX

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“…[88][89][90][91][92] These approaches, as outlined by the Tox21 Federal collaboration and the U.S. Environmental Protection Agency's ToxCast program, [93][94][95][96] can be used to focus high-throughput in vitro and in vivo testing on compounds and concentrations that are more likely to be biologically active and appropriate for each model. Data from more highly characterized products can be integrated into dynamic models, and in vitro to in vivo extrapolation (IVIVE) can be used to predict biological responses.…”

Section: In Silico Modelsmentioning

confidence: 99%

Improving natural product research translation: From source to clinical trial

et al. 2019

Self Cite

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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 Septe mber, 2018 trans disci plina ry workshop. 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. K E Y W O R D S clinical predictive validity, dietary supplements, model systems, rigor and replicability, value of information | 43 SORKIN et al.still provide invaluable guidance, the results of such trials are often met with concerns that different design choiceswhether of product, dose, timing, participant eligibility criteria, outcomes, etc.-might have yielded a substantially different result. Each interventional trial represents a substantial investment, with well-powered Phase III CTs typically consuming more than $10 million and many person-years. 9,10 Additionally, as time and funds are limited, and participant pools may also be constrained, a decision to invest in a CT often precludes pursuing other research questions, 11 which may provide more useful public health-relevant knowledge than an RCT with an insufficient evidence base.

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“…It can help to better characterize the implication of transporters in toxicokinetics of pesticides. For this, currently available IVIVE approaches may, however, need to be refined, as recently underlined . IVIVE likely concerns not only intestinal exposure to pesticides via the diet, which constitutes a major way of pesticide entrance, but also dermal and pulmonary exposure.…”

Section: Emerging Points and Future Directions With Respect To Pesticmentioning

confidence: 99%

“…For this, currently available IVIVE approaches may, however, need to be refined, as recently underlined. 65 IVIVE likely concerns not only intestinal exposure to pesticides via the diet, which constitutes a major way of pesticide entrance, but also dermal and pulmonary exposure. Transporters present at the pulmonary or skin barriers have therefore to deserve special attention.…”

Section: Emerging Points and Future Directions With Respect To Pesticmentioning

confidence: 99%

Implication of human drug transporters to toxicokinetics and toxicity of pesticides

Guéniche

Bruyère

Vée

et al. 2019

Pest Management Science

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Human membrane drug transporters are recognized as major actors of pharmacokinetics. Pesticides also interact with human drug transporters, which may have consequences for pesticide toxicokinetics and toxicity. The present review summarizes key findings about this topic. In vitro assays have demonstrated that some pesticides, belonging to various chemical classes, modulate drug transporter activity, regulate transporter expression and/or are substrates, thus bringing the proof of concept for pesticide‐transporter relationships. The expected low human concentration of pesticides in response to environmental exposure constitutes a key‐parameter to be kept in mind for judging the in vivo relevance of such pesticide‐transporter interactions and their consequences for human health. Existing data about interactions of pesticides with drug transporters remain, however, rather sparse; more extensive and systematic characterization of pesticide‐transporter relationships, through the use of high throughput in vitro assays and/or in silico methods, is, therefore, required. In addition, consideration of transporter polymorphisms, pesticide mixture effects and physiological and pathological factors governing drug transporter expression may help to better define the in vivo relevance of pesticide‐transporter interactions in terms of toxicokinetics and toxicity for humans. © 2019 Society of Chemical Industry

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In vitro to in vivo extrapolation for high throughput prioritization and decision making

Cited by 186 publications

References 110 publications

A human population-based organotypic in vitro model for cardiotoxicity screening

A human population-based organotypic in vitro model for cardiotoxicity screening

Improving natural product research translation: From source to clinical trial

Implication of human drug transporters to toxicokinetics and toxicity of pesticides

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