Resources

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

Milani et al., 2022

This study shows how an in vitro gut-liver multi-organ model can quantitatively recapitulate the in vivo metabolism of a drug. By combining Organ-on-a-chip with in silico modeling, the study also demonstrates the potential of multi-organ models for quantitative estimation of PK parameters of a drug and its metabolites.

Every Breath You Take: Predicting Inhaled Drug ADME Using Lung-on-a-Chip

Webinar Series 5 Episode 2

In this webinar, Lead Scientist, Dr Emily Richardson describes novel alveolar and bronchial lung-on-a-chip, or lung MPS, models. She demonstrates how to predict drug pharmacokinetics, allowing for more rapid, precise, and cost-effective compound analysis.

Why two organs are better than one

Abbas, Kostrzewski & Hughes

This poster demonstrates how a gut-liver MPS can improve oral bioavailability predictions by mimicking human oral and IV regimens. Thus improving the in vitro to in vivo translation of drug efficacy and safety.

A microfluidic system that replicates pharmacokinetic (PK) profiles in vitro improves prediction of in vivo efficacy in preclinical models

Singh et al., 2022

This publication demonstrates the Microformulators capability to incorporate replicated PK exposures into cellular assays to improve in vitro–in vivo translation understanding. This is demonstrated through comparisons to traditional fixed dose in vitro studies and in vivo xenograft models.

Normalization of organ-on-a-chip samples for mass spectrometry based proteomics and metabolomics via dansylation-based assay

Gallagher et al

This poster shows the combined use of MS-based proteomics and metabolomics with organ-on-a-chip to better assess the classification of biological replicates in toxicity studies.

Harnessing the power of multimodal imaging to explore ASO distribution in cells, complex in vitro models and tissue

Alex et al

This recent poster from GSK and collaborators features data from our PhysioMimix™ OOC and Liver (MPS-LC12) plates. The results demonstrate that the distribution of ASOs into Kupffer cells and circular or cuboidal hepatocytes cultured in 3D can be detected using imaging.

Bridging Gaps in Translational Biology

Petreus et al

Developing effective oncology therapies involves defining the right schedules to minimize side effects and maximise efficacy. This requires an accurate understanding of the pharmacokinetic/pharmacodynamics PK/PD relationship of the compound(s). Animal and human PKs can differ significantly and many failures of novel therapies are due to a missing physiologically relevant link between preclinical and clinical data.​

Exploration and Application of a Liver-on-a-Chip Device in Combination with Modelling and Simulation for Quantitative Drug Metabolism Studies

Docci et al., 2022

This publication explores the potential of the PhysioMimix liver model for investigating drug candidates for hepatic disease. This study integrates mathematical modeling with experimental liver-on-a-chip studies and demonstrates how this approach supports the generation of high-quality data from complex in vitro cellular systems.

Multiorgan microphysiological systems as tools to interrogate interorgan crosstalk and complex diseases

Trapecar, 2022

A review of the state of multi-organ microphysiological systems in 2021. Overviews of currently available multi-organ MPS and the different technologies, cells and physiological cues used. Discusses approaches for systems biology integration and how MPS can be more readily adopted in the wider research community.

Predicting Drug Bioavailability with the Modern-Day Toolkit

Animal models continue to be used in bioavailability research but limitations are serious and difficult to overcome. Find out how OOC can help solve your PK/PD and bioavailability issues.

This article is taken from International Biopharmaceutical Industry Winter 2021, pages 14-17.

Improved prediction of oral bioavailability using a gut-liver microphysiological system

Abbas, Kostrzewski & Hughes

Central to the development of new drugs is an understanding of their pharmacokinetic properties, in particular their bioavailability. Here, we demonstrate the potential of a true 2-organ gut-liver MPS to better predict human bioavailability and improve in vitro to in vivo correlation.

From Dose to Circulation: Determination of Drug Oral Bioavailability Using a Gut-Liver Microphysiological System

Webinar Series 4 Episode 4

In this webinar, Dr. Yassen Abbas discusses how CNBio’s gut-liver MPS can be used for in vitro determination of oral bioavailability. This application has been validated with drugs with known human bioavailability and with a mathematical model developed to enable prediction of oral bioavailability in silico.

Drug metabolism in a gut-liver microphysiological system

Abbas, Kostrzewski & Hughes

Studies investigating the efficacy and safety of candidate drugs use a variety of animal models to translate research from the bench to clinical trials and then to the clinic. Here, we demonstrate the potential of multi-organ MPS models for improved predictions of in vivo drug absorption and hepatic clearance rates.

Pharmacokinetic profiles revisited in 3D microfluidic tumour models

Petreus et al

The efficacy or toxicity of a drug is dependent on the concentration at the target. Current preclinical models mainly rely on in vivo animal studies which often lack translatability to the human. Here, we demonstrate the potential of a new in vitro MPS approach to better predict human PK and improve in vitro to in vivo translational relevance.

Predicting human drug permeability with a gut microphysiological system

Bray et al

Preclinical drug absorption studies are a key step when developing when therapeutics as they determine how much of orally-administered drug reaches the systemic circulation. Here, we show how we developed and characterized a gut MPS closely aligned to the human small intestine, using the PhysioMimix™ Single-Organ system, and demonstrated its utility to predict drug permeability.

Microphysiological systems of the human liver, gut and linked liver-gut, to assess human drug absorption, metabolism and bioavailbility

Kostrzewski et al

This poster demonstrates the potential of human MPS models for liver, gut, and multi-organ (connecting gut with liver) for the investigation of human PK parameters, drug absorption and metabolism, and bioavailability.

Liver-on-Chip and In Silico Modeling for Quantitative Drug Metabolism Studies

Webinar Series 4 Episode 1:

This webinar examines the benefits of combining Liver-on-a-chip with in silico modeling to explore clinical PK predictions of specific reference drugs, including investigations into the intrinsic clearance determinations for high metabolically stable compounds and the quantitation of fractions metabolized by specific enzymes.

Bringing Life to PK Profiles: In Vivo-Relevance From an In Vitro Environment.

Webinar Series 3 Episode 4:

In this webinar, we introduce a new MPS platform designed to address these challenges: the PhysioMimix™ PK – a novel microformulator developed by CN Bio

Formulating a New Approach to Pharmacokinetics and Cell State Control

Webinar Series 3 Episode 3:

In this webinar, Professor John Wikswo discusses the need for better approaches to efficiently and better predict pharmacokinetics in vitro.

Towards a Body-on-a-Chip: The Value of Multi-Organ MPS for Human-Relevant Drug Assessment

Webinar Series 3 Episode 1:

In this webinar, Dr Tomasz Kostrzewski, VP – Science & Technology explores how single-and multi-organ MPS can be incorporated into your drug discovery and development workflows to increase in vitro to in vivo translation of preclinical assays.

Multi-Organ in vitro organ-on-chip models for intestinal drug absorption and metabolism

Bray et al

The development of more translationally relevant in vitro intestinal models is key to better predicting drug absorption earlier in the drug development process. Here, we demonstrate the potential of a gut MPS, and a simple gut-liver MPS, for preclinical ADME investigation.

Gut-liver organ-on-a-chip combined with in silico modeling as a promising tool for investigation of mycophenolate mofetil pharmocokinetics

Milano et al

This poster demonstrates the potential of a true 2-organ gut-liver MPS for ADME applications and is more relevant in vitro to in vivo translation of drug efficacy and toxicity.

Testing on Humans How to Predict Hepatotoxicity and Drug Clearance Ahead of Clinical Trials Using Liver-on-a-Chip

Webinar Series 2 Episode 2:

In this webinar, Dr Tomasz Kostrzewski discusses the need for better preclinical in vitro approaches for investigational toxicology, drug metabolism, and safety.

Characterizing the reproducibility in using a liver microphysiological system for assaying drug toxicity, metabolism and accumulation

Rubiano et al., 2020

This study demonstrated the ability of the CN Bio’s PhysioMimix liver model to generate reproducible results from experiments assaying metabolism, drug toxicity and intracellular accumulation. The results from the paper showed that the liver MPS can be routinely used in general drug evaluation applications.

A Regulators Viewpoint: Establishing Strategies To Evaluate Microphysiological Systems for Drug Development

Webinar Series 1 Episode 4

In this webinar, Dr Alexandre Ribeiro, FDA, discusses Regulators’ strategies to evaluate and establish MPS for preclinical drug development.

Investigating the PK/PD/efficacy relationship of PI3K inhibitors in vitro, enabled by a microfluidic addition and removal device

Singh et al

Characterizing the relationship between pharmacokinetics (PK), pharmacodynamics (PD), and efficacy is critical in the discovery and development of new drugs, schedules, and combinations. This study explores an in vitro methodology using a device capable of recapitulating in vivo PK-like profiles in vitro.

In vitro assessment of combination dosing regimen with in vivo-like pharmacokinetic concentration profiles enabled by a microfluidic addition and removal device

Golby et al

The pharmacokinetic (PK) profile is a determining factor in both the safety and efficacy of a drug or therapeutic regimen. PK profiles can vary significantly between patients and between humans and pre-clinical animal species.​

Here we describe a device capable of recapitulating PK-like profiles in vitro and explore the effects of PK on the treatment of non-small-cell lung carcinoma in mono and combination therapy.

Interconnected microphysiological systems for quantitative biology and phamarcology studies

Edington et al., 2018

A proof-of-principle study that demonstrates microphysiological systems are capable of modeling multiple organs enabling pharmacological testing of drugs and assessing organ-organ cross-talk, this was done through measuring functional biomarkers for the liver and brain and TEER for the gut and lungs over time.

Integrated gut and liver microphysiological systems for quantitative in vitro pharmacokinetics studies

Tsamandouras et al., 2017

There is a need for more physiologically-relevant in vitro models to better investigate the efficacy and pharmacokinetics (PK) of compounds in the early stages of drug development. Here, we demonstrate the potential of a multi-organ (gut-liver) MPS combined with quantitative mechanistic modeling to accurately assess the PK of new therapeutics.

Integrated assessment of diclofenac biotransformation, pharmacokinetics and omics-based toxicity in a 3D human liver-immunocompetent co-culture system

Sarkar et al., 2017

The paper demonstrates how 3D liver MPS may serve as preclinical investigational platforms for the discovery of a set of clinically-relevant biomarkers, including potential reactive metabolites, endogenous bile acids, excreted proteins, and cytokines to predict early drug-induced liver toxicity in humans.

Integrated gut/liver microphysiological systems elucidates inflammatory inter-tissue crosstalk

Chen et al., 2017

Animal models are the only way to understand the complex systemic effects of drugs in organisms; however, they often fail to translate to humans. Here, we demonstrate the potential of a multi-organ model to study inflammatory organ crosstalk between the gut and liver.

Multi-functional scaling methodology for translational pharmacokinetic and pharmacodynamic applications using integrated MPS

Maass et al., 2017

Typically scaling for MPS systems is designed upon allometric scaling and not function. This study outlines a new multi-functional scaling method for multi-organ MPS platform design. Explored in this study are Gut-Liver and Gut-Liver-Kidney models.

Quantitative Assessment of Population Variability in Hepatic Drug Metabolism Using a Perfused Three-Dimensional Human Liver Microphysiological System

Tsamandouras et al., 2017

A study which demonstrates the variation of hepatocyte drug metabolism over different donor sets and how this data can be best interpreted translationally using modelling and simulation frameworks. Five donors’ abilities to metabolise six drugs were evaluated alongside metabolism gene and functional viability analysis.

Modeling Therapeutic Antibody-Small Molecule Drug-Drug Interactions Using a Three-Dimensional Perfusable Human Liver Coculture Platform

Long et al., 2016

TBC

Quantitative systems pharmacology approaches applied to MPS: Data interpretation and Multi-MPS integration

Yu et al., 2015

These studies demonstrate the use of MPS for in vitro-to-in vivo translation of pharmacology data.

Metabolite profiling and pharmacokinetic evaluation of hydrocortisone in a perfused 3D human liver bioreactor

Sarkar et al., 2015

Study using glucocorticoids to demonstrate their anti-inflammatory proterties in liver cells cultured with lipopolysaccharied (LPS).

Morphological behaviour and metabolic capacity of cryopreserved human primary hepatocytes cultivated in a perfused multiwell device

Vivares et al., 2015

This study evaluated the viability of a human liver model when cultured on a microfluidic LiverChip™ system. Findings highlighted the system’s ability to maintain healthy morphology and metabolic capacity over the 7-day period in culture, displaying well-differentiated and viable structures of human hepatocytes. This outlined the potential of MPS to be employed as a platform for quantitative prediction in drug studies.

Addressing the Challenges of Low Clearance in Drug Research

Di and Obach, 2015

Current tools available in vitro for early metabolite identification and ADME exploration are limited in low clearance compounds often leading to gross overestimations of clearance. This paper explores improved methodologies in vitro which focus on more accurate in vitro results for low clearance compounds.