Evaluation of seven drug metabolisms and clearances by cryopreserved human primary hepatocytes cultivated in microfluidic biochips

Baudoin, R.; Prot, Jean‐Matthieu; Nicolas, Grégory; Brocheton, Jessy; Brochot, Céline; Legallais, Cécile; Bénech, Henri; Leclerc, Éric

doi:10.3109/00498254.2012.706725

Cited by 42 publications

(42 citation statements)

References 34 publications

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“…Liver-on-a-chip models integrated with physiologically based pharmacokinetic computational models have been particularly useful for predicting rates of metabolic drug clearance that correlate with clinical data 52 . For instance, this integrative liver-on-a-chip approach was used to culture human primary hepatocytes in 12 parallel microfluidic chambers and to test the metabolism of 7 drugs simultaneously 53 . Detection and quantification of drug metabolites revealed that five cytochrome P450 enzymes — mediators of phase I drug metabolism — were active in these systems.…”

Section: Potential Uses In Drug Screeningmentioning

confidence: 99%

Organs-on-chips at the frontiers of drug discovery

Esch

Bahinski

Huh

2015

Nat Rev Drug Discov

1,014

759

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Improving the effectiveness of preclinical predictions of human drug responses is critical to reducing costly failures in clinical trials. Recent advances in cell biology, microfabrication and microfluidics have enabled the development of microengineered models of the functional units of human organs — known as organs-on-chips — that could provide the basis for preclinical assays with greater predictive power. Here, we examine the new opportunities for the application of organ-on-chip technologies in a range of areas in preclinical drug discovery, such as target identification and validation, target-based screening, and phenotypic screening. We also discuss emerging drug discovery opportunities enabled by organs-on-chips, as well as important challenges in realizing the full potential of this technology.

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Section: Potential Uses In Drug Screeningmentioning

confidence: 99%

Organs-on-chips at the frontiers of drug discovery

Esch

Bahinski

Huh

2015

Nat Rev Drug Discov

1,014

759

View full text Add to dashboard Cite

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“…For dynamic parameters (volumetric flow rate, shear rate, drug dosing and clearance) many integrated approaches such as allometric scaling relying on power law scalings across different mammalian species 348–350 , integrated physiologically based pharmacokinetic (PBPK) modeling approaches 275,351–353 and IVIVE approaches 354,355 have been proposed both to guide the parameters as well as work around their limitations when trying to make sense of data.…”

Section: A Critique Of the History And Going Forward: Challenges Amentioning

confidence: 99%

Microengineered cell and tissue systems for drug screening and toxicology applications: Evolution ofin-vitroliver technologies

et al. 2015

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The liver performs many key functions, the most prominent of which is serving as the metabolic hub of the body. For this reason, the liver is the focal point of many investigations aimed at understanding an organism’s toxicological response to endogenous and exogenous challenges. Because so many drug failures have involved direct liver toxicity or other organ toxicity from liver generated metabolites, the pharmaceutical industry has constantly sought superior, predictive in-vitro models that can more quickly and efficiently identify problematic drug candidates before they incur major development costs, and certainly before they are released to the public. In this broad review, we present a survey and critical comparison of in-vitro liver technologies along a broad spectrum, but focus on the current renewed push to develop “organs-on-a-chip”. One prominent set of conclusions from this review is that while a large body of recent work has steered the field towards an ever more comprehensive understanding of what is needed, the field remains in great need of several key advances, including establishment of standard characterization methods, enhanced technologies that mimic the in-vivo cellular environment, and better computational approaches to bridge the gap between the in-vitro and in-vivo results.

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“…The vision is for MPS technologies to provide improved in vitro tools and increased translational success for pharmacokinetic, pharmacodynamic, toxicology and biomarker discovery applications 15–18 . Results from current in vitro models as well as animal models frequently differ from early clinical trial results, and appropriately designed MPSs will most likely represent in vivo tissue and organ biology more adequately.…”

Section: Introductionmentioning

confidence: 99%

Multi-functional scaling methodology for translational pharmacokinetic and pharmacodynamic applications using integrated microphysiological systems (MPS)

Maaß

Stokes²,

Griffith

et al. 2017

Integr. Biol.

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Microphysiological systems (MPS) provide relevant physiological environments in vitro for studies of pharmacokinetics, pharmacodynamics and biological mechanisms for translational research. Designing multi-MPS platforms is essential to study multi-organ systems. Typical design approaches, including direct and allometric scaling, scale each MPS individually and are based on relative sizes not function. This study’s aim was to develop a new multi-functional scaling approach for integrated multi-MPS platform design for specific applications. We developed an optimization approach using mechanistic modeling and specification of an objective that considered multiple MPS functions, e.g., drug absorption and metabolism, simultaneously to identify system design parameters. This approach informed the design of two hypothetical multi-MPS platforms consisting of gut and liver (multi-MPS platform I) and gut, liver and kidney (multi-MPS platform II) to recapitulate in vivo drug exposures in vitro. This allows establishment of clinically relevant drug exposure-response relationships, a prerequisite for efficacy and toxicology assessment. Design parameters resulting from multi-functional scaling were compared to designs based on direct and allometric scaling. Human plasma time-concentration profiles of eight drugs were used to inform the designs, and profiles of an additional five drugs were calculated to test the designed platforms on an independent set. Multi-functional scaling yielded exposure times in good agreement with in vivo data, while direct and allometric scaling approaches resulted in short exposure durations. Multi-functional scaling allows appropriate scaling from in vivo to in vitro of multi-MPS platforms, and in the cases studied provides designs that better mimic in vivo exposures than standard MPS scaling methods.

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Evaluation of seven drug metabolisms and clearances by cryopreserved human primary hepatocytes cultivated in microfluidic biochips

Cited by 42 publications

References 34 publications

Organs-on-chips at the frontiers of drug discovery

Organs-on-chips at the frontiers of drug discovery

Microengineered cell and tissue systems for drug screening and toxicology applications: Evolution ofin-vitroliver technologies

Multi-functional scaling methodology for translational pharmacokinetic and pharmacodynamic applications using integrated microphysiological systems (MPS)

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