New TRISTAN Project Leverages Potential of Imaging Techniques

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New TRISTAN Project Leverages Potential of Imaging Techniques in Drug Safety Assessment

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Press Release

New TRISTAN Project Leverages Potential of Imaging Techniques in Drug Safety Assessment

Brussels, April 12 2017 – The Innovative Medicines Initiative (IMI) has approved the 5-year project TRISTAN focusing on validation of translational imaging methods as potential imaging biomarkers.

TRISTAN (Translational Imaging in Drug Safety Assessment) is a public-private partnership supported by the Innovative Medicines Initiative (IMI) and involving 21 organisations including academics centres, research organisations, small and medium-size enterprises (SMEs), imaging and pharmaceutical companies. The objective of the project is to validate or qualify translational imaging methods as potential imaging biomarkers. The imaging biomarker qualification will be specifically addressed in three areas with a high unmet medical need: the assessment of liver toxicity, lung toxicity and the bio-distribution of biologics. The in-kind contributions to the project of around EUR 12 million by the industrial partners are complemented by IMI-funding in a total budget of EUR 24 million. TRISTAN is led by Bayer and coordinated by the European Organisation for Research and Treatment of Cancer (EORTC), who also leads one imaging biomarker qualification study for cancer drug induced interstitial lung disease.

Imaging techniques are firm components of today’s medical practices, just as the use of biomarkers has become commonplace in pre-clinical and clinical research. However, imaging biomarkers are not widely used in the drug discovery process although they could advance drug safety evaluation, both for pre-clinical and clinical development. Imaging biomarkers have the potential to improve translatability of pre-clinical (animal) data to healthy volunteers and patients and thus could help avoid late stage attrition of development programmes. In addition, functional diagnostic imaging methods used as biomarkers would offer the possibility to confirm drug toxicity mechanisms in humans, including the potential to determine drug-drug interactions.

Data relevant for validation of methods addressed in the project and aggregated data will be made publicly available in compliance with data privacy laws. Significant interactions with existing imaging biomarker initiatives as well as with regulatory authorities will have a strong impact on the future value of imaging biomarker procedures. To sustainably offer access to the validated imaging biomarkers, the three project SME partners are planning to offer respective biomarker imaging services commercially.

About Imaging Biomarkers

An imaging biomarker is a functional radiographic imaging procedure utilising imaging modalities like Computed Tomography (CT), Magnetic Resonance Imaging (MRI), and Positron Emission Tomography (PET). In research and development, imaging biomarkers are used as characteristics to objectively measure biological processes, pathological changes, or pharmaceutical responses to a therapeutic intervention. They have the advantage of remaining non-invasive and being spatially and temporally resolved. Imaging biomarkers have the potential to improve translatability of animal data to healthy volunteers and patients, thereby helping to improve our understanding of drug mechanisms, interactions and metabolic processes.

About the Innovative Medicines Initiative (IMI)

The Innovative Medicines Initiative (IMI) is working to improve health by speeding up the development of, and patient access to, innovative medicines, particularly in areas where there is an unmet medical or social need. It does this by facilitating collaboration between the key players involved in healthcare research, including universities, the pharmaceutical and other industries, small and medium-sized enterprises (SMEs), patient organisations, and medicines regulators. IMI is a partnership between the European Union and the European pharmaceutical industries, represented by the European Federation of Pharmaceutical Industries and Associations (EFPIA). Through the IMI 2 programme, IMI has a budget of EUR 3.3 billion for the period 2014-2024. Half of this comes from the EU’s research and innovation programme, Horizon 2020. The other half comes from large companies, mostly from the pharmaceutical sector; these do not receive any EU funding, but contribute to the projects ‘in kind’, for example by donating their researchers’ time or providing access to research facilities or resources.

The research leading to these results received funding from the Innovative Medicines Initiatives 2 Joint Undertaking under grant agreement No 116106. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.

 

 

 

Partners in TRISTAN

The project is coordinated and led by:

European Organisation for Research and Treatment of Cancer, EORTC (Coordinator)
Bayer (Lead)
Bioxydyn (Co-coordinator)
GlaxoSmithKline (Co-lead)

Other partners
AbbVie
Antaros Medical
Bruker
Chalmers University of Technology
Université de Bourgogne Dijon
GE Healthcare
University Medical Center Groningen
University of Leeds
Lund University
University of Manchester
MSD
Radboud University Nijmegen
Novo Nordisk
Pfizer
Sanofi
University of Sheffield
Truly Labs

More info on IMI: www.imi.europa.eu

PRESS RELEASE
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89Zr-Immuno-Positron Emission Tomography in Oncology

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89Zr-Immuno-Positron Emission Tomography in Oncology: State-of-the-Art 89Zr Radiochemistry.

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89Zr Radiochemistry Review

89Zr-Immuno-Positron Emission Tomography in Oncology: State-of-the-Art 89Zr Radiochemistry.

Heskamp S, Raavé R, Boerman O, Rijpkema M, Goncalves V, Denat F.


Bioconjug Chem. 2017 Aug 24. doi: 10.1021/acs.bioconjchem.7b00325.

Abstract

Immuno-positron emission tomography (immunoPET) with 89Zr-labeled antibodies has shown great potential in cancer imaging. It can provide important information about the pharmacokinetics and tumor-targeting properties of monoclonal antibodies and may help in anticipating on toxicity. Furthermore, it allows accurate dose planning for individualized radioimmunotherapy and may aid in patient selection and early-response monitoring for targeted therapies. The most commonly used chelator for 89Zr is desferrioxamine (DFO). Preclinical studies have shown that DFO is not an ideal chelator because the 89Zr–DFO complex is partly unstable in vivo, which results in the release of 89Zr from the chelator and the subsequent accumulation of 89Zr in bone. This bone accumulation interferes with accurate interpretation and quantification of bone uptake on PET images. Therefore, there is a need for novel chelators that allow more stable complexation of 89Zr. In this Review, we will describe the most recent developments in 89Zr radiochemistry, including novel chelators and site-specific conjugation methods.

89ZR RADIOCHEMISTRY REVIEW
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In vivo models of Drug Induced ILD; tools to study

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In vivo models of Drug Induced ILD; tools to study and improve drug safety (Conference Abstract)

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Conference Abstract: DIILD in vivo models

In vivo models of Drug Induced ILD; tools to study and improve drug safety (Conference Abstract)

Irma Mahmutovic Persson, Hanna Falk Håkansson, Per-Ola Önnervik, Janne Persson, Karin von Wachenfeldt, Lars E. Olsson - on behalf of the TRISTAN Consortium


ERS Lung Science Conference (LSC), 8-11 March 2018, Estoril, Portugal

 

Background

Drug safety is extremely important, yet many drugs on the market have the possibility to induce interstitial lung injury, also known as drug induced interstitial lung disease (DIILD), although they are not administered locally into the lung. Once DIILD starts to develop, patients are normally taken off the drug, and in more severe cases treated with glucocorticoids. As a result, the induced lung injury resolve in many patients while others continue to develop progressive disease. In order to improve drug development in the future, and also to understand how to better treat patients with progressive DIILD, additional studies are required to investigate the underlying mechanisms of e.g. cell and matrix interactions. Well characterized models are needed for evaluation and development of biomarkers in order to better understand and accordingly prevent the progression of DIILD. The work presented here is part of a larger effort supported by IMI aiming at developing and validating pre-clinical imaging biomarkers for DIILD (TRISTAN). As a first step, a robust Bleomycin model is developed by testing various doses of Bleomycin from different manufacturers, along with imaging-monitoring of disease progression correlating this to cell- and histology analyses.

CONFERENCE ABSTRACT: DIILD IN VIVO MODELS
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Noninvasive Preclinical and Clinical Imaging of Liver

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Noninvasive Preclinical and Clinical Imaging of Liver Transporter Function Relevant to Drug-Induced Liver Injury

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DILI Book Chapter

Noninvasive Preclinical and Clinical Imaging of Liver Transporter Function Relevant to Drug-Induced Liver Injury

J. Gerry Kenna, John C. Waterton, Andreas Baudy, Aleksandra Galetin, Catherine D. G. Hines, Paul Hockings, Manishkumar Patel, Daniel Scotcher, Steven Sourbron, Sabina Ziemian and Gunnar Schuetz


In: Chen M., Will Y. (eds) Drug-Induced Liver Toxicity. Methods in Pharmacology and Toxicology. Humana Press, New York, NY doi: 10.1007/978-1-4939-7677-5_30.

 

Abstract

Imaging technologies can evaluate many different biological processes in vitro (in cell culture models) and in vivo (in animals and humans), and many are used routinely in investigation of human liver diseases. Some of these methods can help understand liver toxicity caused by drugs in vivo in animals, and drug-induced liver injury (DILI) which arises in susceptible humans. Imaging could aid assessment of the relevance to humans in vivo of toxicity caused by drugs in animals (animal/human translation), plus toxicities observed using in vitro model systems (in vitro/in vivo translation). Technologies and probe substrates for quantitative evaluation of hepatobiliary transporter activities are of particular importance. This is due to the key role played by sinusoidal transporter mediated hepatic uptake in DILI caused by many drugs, plus the strong evidence that inhibition of the hepatic bile salt export pump (BSEP) can initiate DILI. Imaging methods for investigation of these processes are reviewed in this chapter, together with their scientific rationale, and methods of quantitative data analysis. In addition to providing biomarkers for investigation of DILI, such approaches could aid the evaluation of clinically relevant drug−drug interactions mediated via hepatobiliary transporter perturbation.

DILI BOOK CHAPTER
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In vitro and in vivo comparison of the novel

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In vitro and in vivo comparison of the novel 89Zr chelator DFO-cyclo* with DFO (Conference Abstract)

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Conference Abstract: DFO-cyclo versus DFO

In vitro and in vivo comparison of the novel 89Zr chelator DFO-cyclo* with DFO (Conference Abstract)

Rene Raave, Gerwin Sandker, Sandra Heskamp, Otto Boerman, Mark Rijpkema, Floriane Mangin, Michel Meyer, Jean-Claude Chambron, Mathieu Moreau, Claire Bernhard, Victor Goncalves, Franck Denat


ESRR 18, 19th European Symposium on Radiopharmacy and Radiopharmaceuticals, 05-08 April 2018, Groningen, Netherlands

Abstract

The current “gold standard” chelator to label antibodies with 89Zr for immunoPET is desferrioxamine (DFO). Preclinical studies have shown that the 89Zr-DFO complex is partly unstable in vivo, resulting in release of 89Zr and subsequent accumulation of 89Zr in mineral bone tissue. This bone uptake may prevent the detection of bone metastases, and hampers accurate estimation of the radiation dose to the bone marrow in dose planning for radioimmunotherapy. Therefore, there is a need for a more stable 89Zr chelator. Here we report DFO-cyclo*, a preorganized extended DFO derivative introducing an octacoordination, and investigate the stability of its 89Zr complex over the unsaturated hexacoordinated 89Zr-DFO complex in vitro and in vivo.

CONFERENCE ABSTRACT: DFO-CYCLO VERSUS DFO
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Gadoxetate relaxivities increase significantly after hepatic

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Gadoxetate relaxivities increase significantly after hepatic uptake at clinical field strength impacting kinetic modelling for liver function analysis (Conference Abstract)

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Conference Abstract: Gadoxetate relaxivity in liver

Gadoxetate relaxivities increase significantly after hepatic uptake at clinical field strength impacting kinetic modelling for liver function analysis (Conference Abstract)

Gregor Jost, Gunnar Schuetz, Hubertus Pietsch


ISMRM Annual Meeting 2018, 16-21 June 2018,Paris, France

 

Abstract

Gadoxetate has been clinically approved for detection and characterization of focal liver lesions by MRI. It exhibits moderate protein binding and is excreted from the body partially through the kidneys and partially by a hepatobiliary pathway. Hepatocytes take up gadoxetate mainly via OAPT and NTCP transporters and excrete it into the bile mainly utilizing Mrp2. By means of dynamic acquisition of gadoxetate signal intensity during liver uptake and excretion followed by application of a suitable kinetic model, the activity of the aforementioned liver transporters can be estimated. For kinetic modelling the gadoxetate concentration for each time point is needed which can be calculated from the signal intensity if r1 in tissue is known. In 1992 Schuhmann-Giampieri et al. reported r1 of gadoxetate to be significantly higher in liver tissue compared to blood at 0.47T. This effect has been attributed to gadoxetate’s protein binding which leads to an increased rotational correlation time. Gadoxetate relaxivities at 1.5T, 3T and 4.7T have since then been reported for water and plasma, but not for hepatocytes. We here present relaxivities for gadoxetate in hepatocytes at 1.5T and 3T to complement the original Schuhmann-Giampieri data. Measurements at 7T are in progress. Interestingly, r1 of gadoxetate after uptake into hepatocytes is about 2x higher compared to plasma and does not decrease with increasing field strength as has been shown for high relaxivity Gd based contrast agents exhibiting high protein binding e.g. gadofosveset. Gadoxetate’s higher r1 in hepatocytes has to be taken into account for pharmacokinetic modelling of dynamic gadoxetate MRI at clinical field strength, which has not been done so far.

CONFERENCE ABSTRACT: GADOXETATE RELAXIVITY IN LIVER
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Overview of the TRanslational Imaging in Drug SafeTy

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Overview of the TRanslational Imaging in Drug SafeTy AssessmeNt (TRISTAN) IMI Consortium and Progress towards Standardization of MR Biomarkers of Liver Injury and Drug-Drug Interactions (Conference Abstract)

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Conference Abstract: DILI imaging biomarkers

Overview of the TRanslational Imaging in Drug SafeTy AssessmeNt (TRISTAN) IMI Consortium and Progress towards Standardization of MR Biomarkers of Liver Injury and Drug-Drug Interactions (Conference Abstract)

Aleksandra Galetin, Claudia Green, Catherine Hines, Paul Hockings, Lisa Jarl, Gerry Kenna, Sascha Koehler, Iina Laitinen, Xiangjun Meng, Corin Miller, Kayode Ogungbenro, Geoff Parker, Ian Rowe, Gunnar Schuetz, Daniel Scotcher, Steven Sourbron, Klaus Strobel, Sirisha Tadimalla, Ekaterina Tankisheva, John Waterton, Sabina Ziemian


In Vivo MR Gordon Research Conference, 15-20 July 2018, Andover, NH, USA

 

Abstract

In 2017, the TRanslational Imaging in Drug SafeTy AssesmeNt (TRISTAN) Innovative Medicines Initiative (IMI) consortium commenced to leverage the potential of imaging techniques to improve drug safety analysis and translatability of findings by validating and making available imaging procedures as assays to provide biomarkers for widespread use. As such, hepatobiliary transporter assessment is being undertaken using gadoxetate-enhanced MRI-derived biomarkers. Gadoxetate is known to be a substrate for the human influx transporters OATP1B1, OATP1B3, and NTCP, and the efflux transporters MRP2 and MRP3, and their rat orthologues. These transporters contribute to relevant transporter-mediated drug-drug interactions and mediate hepatobiliary clearance of numerous drugs which cause drug-induced liver injury. In addition, inhibition of bile acid excretion by drugs is an important mechanism by which drug-induced liver injury can be initiated. In view of this, the authors seek to validate influx and efflux rates of gadoxetate as an imaging biomarker assay for in vivo liver transporter assessment.

CONFERENCE ABSTRACT: DILI IMAGING BIOMARKERS
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Systematic review: In vivo imaging in animal models

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Systematic review: In vivo imaging in animal models relevant to drug-induced Interstitial lung disease (DIILD) (Conference Abstract)

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Conference Abstract: DIILD Animal Models

Systematic review: In vivo imaging in animal models relevant to drug-induced Interstitial lung disease (DIILD) (Conference Abstract)

Irma Mahmutovic Persson, Karin von Wachenfeldt, Kashmira Pindoria, Michael Haase, Simon Campbell, Juan X. Delgado, Mark Wright, John C. Waterton and Lars E. Olsson - on behalf of the TRISTAN Consortium


European Respiratory Society, International Congress 2018, 15-19 September 2018, Paris, France

 

Abstract

Translational Imaging Biomarkers (IB) are needed to avoid or manage drug-toxicity, resulting in drug-induced interstitial lung disease (DIILD). We reviewed the literature on in vivo imaging to detect and assess lung lesions in animal models with relevance to DIILD and with pathological changes resembling clinical DIILD.

CONFERENCE ABSTRACT: DIILD ANIMAL MODELS
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Imaging biomarkers of oedema and fibrosis in a rat

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Imaging biomarkers of oedema and fibrosis in a rat model of Drug-Induced Interstitial Lung Disease (DIILD) (Conference Abstract)

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Conference Abstract: Imaging of DIILD in rats

Imaging biomarkers of oedema and fibrosis in a rat model of Drug-Induced Interstitial Lung Disease (DIILD) (Conference Abstract)

Irma Mahmutovic Persson, Anders Örbom, Per-Ola Önnervik, Karin von Wachenfeldt and Lars E. Olsson- on behalf of the TRISTAN Consortium


European Respiratory Society, International Congress 2018, 15-19 Septembr 2018, Paris, France

 

Background

Drugs used to treat various diseases may induce lung injury known as drug induced interstitial lung disease (DIILD). Clinical and pre-clinical studies within the TRISTAN-consortium are aimed at finding translational Imaging Biomarkers (IB) that can indicate progression of DIILD at an early stage. In the present in vivo study, magnetic resonance imaging (MRI) was applied along with analyses of lavage and lung tissue.

CONFERENCE ABSTRACT: IMAGING OF DIILD IN RATS
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Slow infusion improves precision of liver function

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Slow infusion improves precision of liver function measurements by DCE-MRI (Conference Abstract)

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Conference Abstract: Slow infusion dce-mri

Slow infusion improves precision of liver function measurements by DCE-MRI (Conference Abstract)

Sirisha Tadimalla and Steven Sourbron


The British Chapter of ISMRM Annual Meeting, 24-26 September 2018, Somerville College, Oxford

 

Background

Quantitative dynamic contrast-enhanced (DCE) MRI with a rapidly injected bolus of gadoxetate can be used to quantify liver perfusion and transporter function [1,2]. Measuring these rapid changes requires high temporal resolution, and this involves compromises in spatial resolution, coverage or SNR. However, when the aim is to measure hepatocellular function (a slow process), rather than perfusion (a fast process), there is no rationale for a rapid injection.

CONFERENCE ABSTRACT: SLOW INFUSION DCE-MRI
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