Exploration and application of a liver-on-a-chip device in combination with modelling and simulation for quantitative drug metabolism studies

Docci, Luca; Milani, Nicoló; Ramp, Thomas; Romeo, Andrea A.; Godoy, Patrício; Franyuti, Daniela Ortiz; Kraehenbuehl, Stephan; Gertz, Michael; Galetin, Aleksandra; Parrott, Neil; Fowler, Stephen

doi:10.1039/d1lc01161h

Cited by 35 publications

(52 citation statements)

References 58 publications

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“…9 In both studies, the authors reported modeling of experimental data to estimate PK parameters, but did not use drugs for which intestinal compartment metabolism played an important role. 3,4 The work presented in this paper builds upon these achievements, other MPS work involving prodrugs 10,11 and also our recently reported liver-on-a-chip MPS validation work, 6 with particular emphasis on the mechanistic study of prodrug absorption and activation in the gut, a highly relevant ADME application for gut–liver MPS.…”

Section: Introductionmentioning

confidence: 89%

“…Cryopreserved hepatocytes were seeded in the scaffold in the liver compartment as reported previously. 6 A detailed description of the system preparation and incubation methods is provided in the ESI. †…”

Section: Biological Systems In the Gut And Liver Mps Compartmentsmentioning

confidence: 99%

“…The surface of the scaffold was then thoroughly scratched with a pipette tip to ensure maximal retrieval of cells, and the lysing process was continued for half an hour. 6 This process was repeated twice to ensure complete detachment and lysis of the cells. After the scaffold was washed and removed from the cell lysate, total protein concentration was measured with the Pierce™ BCA Protein Assay Kit (Thermo Fisher Scientific), and the incubation cell number calculated using a conversion factor of 1 mg protein per million hepatocytes, as determined previously.…”

Section: Post Incubation Measurementsmentioning

confidence: 99%

“…5 Another important benefit of MPS is the prolonged cell viability which permits extended incubations. 6 For example, Rubiano et al recently reported viability of more than 18 days using a liver-on-a chip device. 7 Long term incubations enable measurement of the biotransformation of metabolically stable compounds and metabolite formation.…”

Section: Introductionmentioning

confidence: 99%

“…In the liver compartment, a flow system distributed drug and media and provided shear stress to the hepatocytes which helped in maintenance of cell viability and phenotype, as reported previously. 6,7,18…”

Section: Introductionmentioning

confidence: 99%

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Application of a gut–liver-on-a-chip device and mechanistic modelling to the quantitative in vitro pharmacokinetic study of mycophenolate mofetil

et al. 2022

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Section: Introductionmentioning

confidence: 89%

Section: Biological Systems In the Gut And Liver Mps Compartmentsmentioning

confidence: 99%

Section: Post Incubation Measurementsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Application of a gut–liver-on-a-chip device and mechanistic modelling to the quantitative in vitro pharmacokinetic study of mycophenolate mofetil

et al. 2022

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Considerations from an International Regulatory and Pharmaceutical Industry (IQ MPS Affiliate) Workshop on the Standardization of Complex In Vitro Models in Drug Development

Tomlinson,

Ramsden,

Leite

et al. 2023

Advanced Biology

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In May 2022, there is an International Regulatory and Pharmaceutical Industry (Innovation and Quality [IQ] Microphysiological Systems [MPS] Affiliate) Workshop on the standardization of complex in vitro models (CIVMs) in drug development. This manuscript summarizes the discussions and conclusions of this joint workshop organized and executed by the IQ MPS Affiliate and the United States Food and Drug Administration (FDA). A key objective of the workshop is to facilitate discussions around opportunities and/or needs for standardization of MPS and chart potential pathways to increase model utilization in the context of regulatory decision making. Participation in the workshop included 200 attendees from the FDA, IQ MPS Affiliate, and 26 global regulatory organizations and affiliated parties representing Europe, Japan, and Canada. It is agreed that understanding global perspectives regarding the readiness of CIVM/MPS models for regulatory decision making and potential pathways to gaining acceptance is useful to align on globally. The obstacles are currently too great to develop standards for every context of use (COU). Instead, it is suggested that a more tractable approach may be to think of broadly applicable standards that can be applied regardless of COU and/or organ system. Considerations and next steps for this effort are described.

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In silico modeling and simulation of organ‐on‐a‐chip systems to support data analysis and a priori experimental design

Milani,

Parrott,

Galetin

et al. 2024

CPT Pharmacom & Syst Pharma

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Organ‐on‐a‐chip (OoC) systems are a promising new class of in vitro devices that can combine various tissues, cultured in different compartments, linked by media flow. The properties of these novel in vitro systems linked to increased physiological relevance of culture conditions may lead to more in vivo‐relevant cell phenotypes, enabling better in vitro pharmacology and toxicology assessment. Improved cell activities combined with longer lasting cultures offer opportunities to improve the characterization of absorption, distribution, metabolism, and excretion (ADME) processes, potentially leading to more accurate prediction of human pharmacokinetics (PKs). The inclusion of barrier tissue elements and metabolically competent tissue types results in complex concentration‐time profiles (in vitro PK) for test drugs and their metabolites that require appropriate mathematical modeling of in vitro data for parameter estimation. In particular, modeling is critical to estimate in vitro ADME parameters when multiple different tissues are combined in a single device. Therefore, sophisticated in silico data analysis and a priori experimental design are highly recommended for OoC experiments in a manner not needed with standard ADME screening. The design of the experiment should be optimized based on an investigation of the structural characteristics of the in vitro system, the ADME features of the test compound and any available knowledge of cell phenotypes. This tutorial aims to provide such a modeling framework to inform experimental design and refine parameter estimation in a Gut‐Liver OoC (the most studied multi‐organ systems to predict the oral drug PKs) to improve translatability of data generated in such complex cellular systems.

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Exploration and application of a liver-on-a-chip device in combination with modelling and simulation for quantitative drug metabolism studies

Abstract: Microphysiological systems (MPS) are complex and more physiologically realistic cellular in vitro tools that aim to provide more relevant human in vitro data for quantitative prediction of clinical pharmacokinetics while...

Cited by 35 publications

References 58 publications

Application of a gut–liver-on-a-chip device and mechanistic modelling to the quantitative in vitro pharmacokinetic study of mycophenolate mofetil

Application of a gut–liver-on-a-chip device and mechanistic modelling to the quantitative in vitro pharmacokinetic study of mycophenolate mofetil

Considerations from an International Regulatory and Pharmaceutical Industry (IQ MPS Affiliate) Workshop on the Standardization of Complex In Vitro Models in Drug Development

In silico modeling and simulation of organ‐on‐a‐chip systems to support data analysis and a priori experimental design

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