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Learnings for Imaging Biomarkers in ILD

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12.03.2024

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Imaging biomarkers in ILD - what we learnt from the TRISTAN study (Conference Abstract)

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Learnings for Imaging Biomarkers in ILD

Imaging biomarkers in ILD - what we learnt from the TRISTAN study - PRO 03-04

by Paul J.C. Hughes, James A. Eaden, Marta Tibiletti, Nazia Chaudhuri, Sarah Skeoch, Ian N. Bruce, John C. Waterton, Stephen Bianchi, Geoff J. Parker, Jim M. Wild on behalf of the TRISTAN Consortium

EMIM 2024

Abstract

Interstitial lung disease (ILD) encompasses a diverse spectrum of pulmonary pathologies, characterized by a combination of clinical, radiographic, and physiological or pathological features. In ILDs, inflammatory and/or fibrotic alterations affect not only the interstitial space but also extend to involve the alveolar structures, alveolar ducts, and bronchioles1.
The TRISTAN study enrolled patients diagnosed with various ILDs including idiopathic pulmonary fibrosis (IPF), connective tissue disease-related ILD (CTD-ILD), hypersensitivity pneumonitis (HP), idiopathic nonspecific interstitial pneumonia (iNSIP), and drug-induced ILD (DI-ILD) and conducted etrospective research into patients with DI-ILD and Hodgkin’s lymphoma. This comprehensive selection of ILDs was made due to the ongoing diagnostic challenges associated with these conditions, necessitating multidisciplinary evaluations incorporating clinical history, pulmonary function tests, immune profiling, computed tomography (CT), and, where feasible, histological examination of lung tissue.
While computed tomography (CT) offers superior resolution compared to alternative imaging modalities such as nuclear medicine or magnetic resonance imaging (MRI), it remains challenging to differentiate between subtypes of ILD in approximately 50% of patients2, and extracting functional data from standard CT imaging poses difficulties. Pulmonary function tests (PFTs), notably assessing forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO), provide global measures of lung function but fail to offer detailed functional information3, highlighting the necessity for enhanced imaging biomarkers.
The TRISTAN study employed various imaging biomarkers derived from CALIPER4 analysis of CT images in conjunction with hyperpolarized xenon-129 (129Xe) and oxygen-enhanced MRI parameters for lung function evaluation, as well as dynamic contrast-enhanced (DCE) proton MRI metrics for lung perfusion assessment. This study aimed to investigate the correlations between these novel imaging biomarkers and PFT results, aiming to ascertain whether superior diagnostic and prognostic capabilities could be achieved compared to current ILD assessment methods. Building upon insights gained from the primary study, a new MR imaging protocol was developed to evaluate patients undergoing bleomycin treatment.
In my presentation, I will delve into the clinical aspects of the TRISTAN project, detailing the imaging methodologies employed and presenting preliminary results from the initial analysis of the data collected and analysed by the clinical members of the consortium.

Learnings for Imaging Biomarkers in ILD

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Imaging Biomarkers of Lung Injury and DIILD

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12.03.2024

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Imaging Biomarkers of Lung Injury and drug-induced ILD: translational approach in experimental research for better disease understanding (Conference Abstract)

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Imaging Biomarkers of Lung Injury and DIILD

Imaging Biomarkers of Lung Injury and drug-induced ILD: translational approach in experimental research for better disease understanding - PRO 03-03

by Irma Mahmutovic Persson on behalf of the TRISTAN Consortium

EMIM 2024

Abstract

To address the increasing issue of drug-induced toxicity, both clinical and experimental studies (within the EU-IHI funded project TRISTAN) are aiming to find translational Imaging Biomarkers that can identify incidence as well as reveal progression of lung injury at an early stage. Together within TRISTAN we are aiming to improve drug safety by development of novel imaging biomarkers. Various imaging techniques such as MRI, PET and CT are used for lesion assessment in lungs of patients and animal models of ILD.
The animal models developed to mimic the clinical aspects of disease have their limitations and opportunities – and the same goes for imaging biomarker development. Many previously promised applications known from oncology and brain-imaging are yet difficult to directly transfer to lung imaging. Many aspects of organ movement, influence of anaesthesia compounds and duration of scan acquisition, needs to be further optimised and automated for better and faster output of accurate data (1). Longitudinal imaging sessions and more non-invasive imaging approach is warranted in order to find the best diagnostic imaging biomarkers. In particular interest are those biomarkers that can characterize and diﬀerentiate inﬂammation from ﬁbrosis within the lung.
In our experimental setting, we have employed the bleomycin-induced injury models in rats and mice and applying different MRI sequences combined with PET-CT imaging co-registration (2). By varying between different Ultra Short Echo (UTE) sequences, lesions of different characteristics can easily be visualized. With the PET-tracer [F18]FDG, typically used in inflammation-imaging, we could see increased signal uptake, significantly higher in bleomycin-challenged lungs compared to healthy controls during the early time points post-injury. However, also a late-phase [F18]FDG-uptake has been observed which is suggested to occur due to active fibrotic processes, similar to tumour metabolism known as the Warburg effect. Since the fibrogenesis might start early while the inflammatory phase is present in this type of model, we aimed to track fibrogenesis with two other, more specific, PET-tracer.
We have performed targeting of collagen type I and fibroblast activation (FAP), at various time points in the lung tissue, using the same bleomycin model in rats (2-4). Both studies were performed according to the same workflow of multi-modality approach with combined MRI/PET/CT longitudinal imaging post-instillation of bleomycin in rats. The Collagen-I tracer named CBP was conjugated to the radionuclide Cu64 while the FAP-tracer included the radionuclei Zr89. The collagen tracer uptake, targeting newly synthesised Collagen-I, was significantly increased in bleomycin-challenged lungs compared to controls, both at early and late time points. The majority of the CBP lung uptake was found at the borderline of MRI- and CT-defined lesions. This was further confirmed by autoradiography, thus on a microscopic level. The other fibrogenesis PET-tracer is targeting the fibroblast activation protein. This study in particular aimed to test the reproducibility of the bleomycin model, being confirmed by histology and cell data but also in parallel followed by [F18]FDG-imaging across the research sites Lund University and Radboud University in Nijmegen (Figure 1). Furthermore, the novel PET tracer tracking early signs of fibrosis onset was investigated, showing promising ability to detect fibroblast activation already 2 weeks after injury, while inflammation still might be present (4).
The intratracheal model has its limitations for certain ILD groups seen in the clinical settings, such as the incidence scenario observed in patients developing drug-induced ILD over time upon bleomycin treatment (5). Therefore, we are also developing animal models where systemic and chronic exposure of bleomycin is performed while also looking into other drug-induced pathologies occurring from other medication classes known to induce ILD in patient cohorts (6: see Figure 2).

Conclusion: As technology is advancing and imaging becomes more available, we have to keep pushing the animal models and imaging biomarkers forward, for better and more relevant readouts. Investing the effort in development of more translational models will bring more knowledge and will become more suitable for studies on intervention and therapeutic titrations.

Imaging Biomarkers of Lung Injury and DIILD

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Liver Transporter Assessment via DCE-MRI

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12.03.2024

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Liver Transporter Assessment via DCE-MRI in Preclinical and Clinical Settings (Conference Abstract)

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Liver Transporter Assessment via DCE-MRI

Liver Transporter Assessment via DCE-MRI in Preclinical and Clinical Settings - PRO 03-02

by Eve S. Shalom on behalf of the TRISTAN Consortium

EMIM 2024

Abstract

Improvement in the non-invasive assessment of hepatocellular function is needed for risk assessment of Drug-Drug Interactions (DDIs) and detection of Drug Induced Liver Injury (DILI) [1]. Many DDIs arise due to perpetrator drugs causing inhibition or induction of hepatic uptake or excretion of victim drugs, which can impact on their efficacy and toxicity. DILI can be caused by inhibited biliary excretion of a victim drug due to harmful accumulation within hepatocytes.

Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) with Gadoxetate offers a potential avenue to probe risk assessment for DDIs and DILI [2], as Gadoxetate is a substrate for several hepatic transporters. TRISTAN Work Package 2 (WP2) focuses on the development of a standardised Gadoxetate DCE-MRI “biomarker” [3] including multi-centre phantom and animal studies to determine translatability of findings to humans.

Recent preclinical work from TRISTAN WP2 has focused on the assessment of sensitivity and reproducibility in identification of hepatocellular uptake and biliary excretion rates across multiple sites and field strengths, to deduce key points of variability. Rat subjects were assessed for the proposed biomarkers with and without six known liver inhibitors with the resulting values assessed. Issues in reproducibility were reported with significant differences between substudies for hepatocellular uptake and biliary excretion rates. However, hepatocellular uptake and biliary excretion rates were found to be above such detection limits for potent liver inhibitor drugs.

Within clinical settings, a study with healthy volunteers has been carried out by TRISTAN WP2 to assess sensitivity of the methodology with the effect of Rifampicin, a known liver inhibitor [4], on the derived hepatocellular biomarker values. The volunteers had DCE-MRI scans consisting of two investigations: (1) a baseline visit and (2) a follow up visit with Rifampicin administered prior scanning. The method reported a measurable and statistically significant reduction of both hepatocellular uptake and biliary excretion rates when Rifampicin was administered.

Both the preclinical and clinical work carried out in WP2 aim to contribute to evidence showing the potential benefit of biomarkers for hepatocyte uptake and biliary efflux for the risk assessment of DILI and DDI in both preclinical and clinical settings. This talk will cover details of these investigations which were undertaken as part of TRISTAN WP2 activities.

Liver Transporter Assessment via DCE-MRI

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Imaging of Harm

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12.03.2024

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Imaging of harm: why we need translational imaging biomarkers in drug safety safety assessment (Conference Abstract)

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Imaging of Harm

Imaging of harm: why we need translational imaging biomarkers in drug safety safety assessment - PRO 03-01

by John W. Waterton on behalf of the TRISTAN Consortium

EMIM 2024

Abstract

Imaging metrics ("biomarkers"[1]) have a prominent role in predicting and detecting treatment benefit, for example as pharmacodynamic biomarkers or as companion diagnostics. However, all treatments involve risk of harm as well as possible benefit, so imaging biomarkers of harm or risk of harm (so-called "safety" biomarkers) are of equal or greater value than imaging biomarkers of treatment efficacy.
Imaging biomarkers of safety can be used in several ways. In toxicology studies in animals they can identify toxicity, determine therapeutic margin, or evaluate reversibility. In human trials, they can be used to halt dose escalation before overt toxicity, to characterise rare adverse events, or to evaluate reversibility. More generally, imaging biomarkers of safety can be used to monitor patients at risk of harm, so that treatment can be adjusted, or to deny particular treatments to patient at risk of harm from that treatment.
The development, validation and deployment of such biomarkers poses unique challenges. While efficacy biomarkers can easily be investigated in patients who elect to receive beneficial therapies, it is often ethically difficult or impossible to deliberately expose human subjects to harmful therapies. Moreover, to prepare for the case of rare and sporadic adverse events, the biomarker needs to be reproducibly available in any hospital in the world where the biomarker might be needed.
Imaging biomarkers of safety are particularly prominent in oncology, in Alzheimer's research, in neurology and rheumatology[2]. This work[3] aims to discover and develop imaging safety biomarkers addressing: harmful changes in liver transporter fluxes, maldistribution (with potentially harmful consequences) of biologic therapies, and drug-induced interstitial lung disease.

Imaging of Harm

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Assessing BSEP by 18F-FCA in rats

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05.09.2023

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Formulation effects of Bile Salt Export Pump inhibitor Bosentan and its in vivo PET Imaging assessment using 18F-3β-Fluoro cholic acid (18F-FCA) in male rats (Conference Abstract)

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Assessing BSEP by 18F-FCA in rats

Formulation effects of Bile Salt Export Pump inhibitor Bosentan and its in vivo PET Imaging assessment using 18F-3β-Fluoro cholic acid (18F-FCA) in male rats

by Bhasker Radaram, Tinamarie Skedzielewski, Stephen Lenhard, Tolulope Aweda, Shih-Hsun Cheng, Glenn Moran, Andrew Gehman, Simon Campbell, Hasan Alsaid on behalf of the TRISTAN Consortium

WMIC 2023

Abstract

Introduction: Bile acids are amphiphilic steroid derivatives produced by hepatocytes that play a key role in digestion of lipids and uptake of fat-soluble vitamins. Bile Salt Export Pump (BSEP) is an efflux transporter that plays a critical role in the secretion of bile salts into the bile. In many species such as humans and rodents, cholic acid is the largest key constituent of the bile acid spectrum. Inhibition of BSEP function by drugs such as Bosentan has resulted in the buildup of bile salts in the liver and lead to drug-induced liver injury (DILI). Formulation of drugs in DMSO (Dimethyl Sulfoxide) poses a safety risk in rodents . To better mitigate the formulation challenges for animal safety, herein, we report the formulation effects of Bosentan in PEG400 and assessed by 18F-3β-Fluorocholic acid (18F-3β-FCA) to examine hepatobiliary transport in vivo in the presence and absence of BSEP inhibitor Bosentan.

Methods: All animal procedures complied with the guidelines of the Institutional Animal Care and Use Committee at GSK following the guidance of Animal Use. 18F-3β-FluoroCholic Acid (18F-FCA) was produced as per literature procedure using an automated ELIXYS Box (Sofie Biosciences, Inc). Wistar (Han) IGS white (albino) outbred male rats (strain 273), 6-11 weeks old with the body weights of 250-410 g were randomized in control (no treatment) and Bosentan treated groups. All animals were fasted for at least 4 hrs before PET imaging to reduce tracer metabolic variability. Rats in the Bosentan treated group (n=4) received 50 mg/Kg Bosentan in PEG400 (iv slow bolus infusion (0.2 mL/min) 1 hr prior to PET imaging. Dynamic PET imaging was acquired using the Mediso LFER150 PET scanner for 1 hr starting with iv injection of 18F-3β-FCA (400 µCi per rat in 200 µL 8% EtOH/PBS). At the end of the PET data acquisition, blood samples were collected for total bile salt analysis. Statistical analysis was performed using two sample t-test with equal variances.

Results: 18F-FCA radiosynthesis was achieved with radiochemical yields (RCY) of 6.64±0.64% (d.c) (n=9) with high radiochemical purity (>99%). Formulation of Bosentan in PEG400 was tolerated in all animals with no sign of pain or distress. However, the Bosentan treated group did not show any inhibition (mean 18F-FCA uptake) compared to the control group (figure 1a) and effluxed to the gallbladder and intestines. The total bile salt analysis was two folds greater in the Bosentan treated group compared to the control group although this difference was not statistically significant.

Conclusions: In summary, Bosentan in the PEG400 formulation improved the tolerability and animal safety compared to the 100% DMSO formulation. However, it did not show a BSEP inhibition compared to the previously published Bosentan formulation in 100% DMSO.

Assessing BSEP by 18F-FCA in rats

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Qualified imaging biomarkers

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01.06.2023

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Towards a qualified imaging biomarker of liver transporter function (Conference Presentation)

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Qualified imaging biomarkers

Towards a qualified imaging biomarker of liver transporter function

by John C Waterton on behalf of the TRISTAN Consortium

EMIM 2023

Abstract

Drugs and other xenobiotics are commonly eliminated via the liver. Uptake by the hepatocyte, and subsequent efflux, involves several transporters with different specificities. If a drug's uptake is perturbed, a drug may be cleared less (or more) rapidly from the blood, leading to harmful overdosing or alternatively lack of efficacy. Where one drug inhibits or enhances the uptake flux of a second drug, this is called a Drug-Drug Interaction (DDI). DDIs can complicate the safe prescribing of medicines to patients who require different drugs which are substrates for the same transporter. If its efflux is inhibited, harmful levels of drug may accumulate in the hepatocyte leading to drug-induced liver injury (DILI).

While hepatocyte uptake and efflux kinetics cannot be unambiguously determined from blood levels, imaging biomarkers from nuclear medicine or MR can provide more specificity (1). Gadoxetate, a MR contrast agent with regulatory approval in most jurisdictions, has previously proved useful in this context.

Drug developers and regulatory authorities are very unlikely to rely on such imaging biomarkers unless they trust the acquisition, analysis and interpretation. In particular they must be highly confident that an apparently negative finding ("drug does not perturb liver transporter fluxes") is a true indication of the drug's safety, and not an artefact of quirks in the methodology or irreproducibility between centres. To address this, FDA established its biomarker qualification program (BQP) to provide confidence in the biomarker data in a specific context of use. Of note, of the 58 biomarkers listed in the qualification programme, a high proportion (31%) are imaging biomarkers and an equally high proportion (31%) are safety biomarkers, suggesting the importance of this route for imaging biomarkers of safety (i.e. lack-of-harm).

Qualified imaging biomarkers

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Assess Drug-induced inhibition of liver function

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01.06.2024

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Measurement of drug-induced inhibition of liver function with dynamic gadoxetate-enhanced MRI: a validation study in healthy volunteers (Conference Abstract)

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Assess Drug-induced inhibition of liver function

Measurement of drug-induced inhibition of liver function with dynamic gadoxetate-enhanced MRI: a validation study in healthy volunteers

by Thazin Min, Marta Tibiletti, Paul Hockings, Alexandra Galetin, Ebony Gunwhy, Gerry Kenna, Nicola Melillo, Geoff Parker, Gunnar Schuetz, Daniel Scotcher, John Waterton, Ian Rowe, Steven Sourbron on behalf of the TRISTAN Consortium

ISMRM 2024

Abstract

Numerous clinically relevant drug-drug interactions (DDIs) arise via inhibition or induction of hepatic uptake or excretion of victim drugs, which may impact on their efficacy and toxicity. DDIs are assessed during drug development by a combination of in-vitro and in-silico methods, but predictions are difficult to verify clinically – especially when DDIs arise via inhibition of the liver’s excretory function. Consequently, clinical trials risk either underestimating DDIs, and so potentially harming study subjects, or overestimating DDI’s and consequently failing to show efficacy.

This reveals a critical need for noninvasive methods which may be used to determine drug exposure within the tissue of interest in vivo. Preclinical studies in rats have shown that drug-induced inhibition of liver uptake and excretion can be measured with dynamic gadoxetate-enhanced MRI [1]. The aim of this study was to verify whether this finding translates to humans, by measuring the change in liver gadoxetate uptake and excretion after administration of rifampicin, a known inhibitor drug.

Assess Drug-induced inhibition of liver function

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Lung perfusion imaging

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01.06.2023

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Lung perfusion imaging: influence of signal-to-concentration transformation method and comparison with 129Xe biomarkers (Conference Abstract)

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Lung perfusion imaging

Lung perfusion imaging: influence of signal-to-concentration transformation method and comparison with 129Xe biomarkers

by Marta Tibiletti, Paul JC Hughes, James A Eaden, Josephine H Naish, Helen A Marshall, John C Waterton, Stephen A Bianchi, Jim M Wild, and Geoff JM Parker on behalf of the TRISTAN Consortium

ISMRM 2023

Abstract #1209

Quantitative pulmonary perfusion can be derived from MR imaging with injection of contrast agent (CA). Tracer-kinetic theory yields physiological parameters such as pulmonary blood flow (PBF), blood volume (PBV) and mean transit time (MTT) but relies on accurate calculation of CA concentration. Previous studies have used ‘subtraction’ or ‘normalisation’ methods without T1-mapping. Using both simulations and data from interstitial lung disease patients, we demonstrate how the ‘subtraction’ method weights PBV by local lung density. This causes likely spurious correlations with hyperpolarised 129Xe biomarkers linked to lung ventilation, microstructure and density, potentially obscuring information of diagnostic interest.

Lung perfusion imaging

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AIF for tracer kinetic modelling

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01.06.2023

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Arterial input function selection for tracer kinetic modelling in rat liver: individual-, population-, or model-derived? (Conference Abstract)

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AIF for tracer kinetic modelling

Arterial input function selection for tracer kinetic modelling in rat liver: individual-, population-, or model-derived?

by Ebony R. Gunwhy, Steven Sourbron, Sirisha Tadimalla, Catherine D. G. Hines, Claudia Green, Iina Laitinen, Paul D. Hockings, Gunnar Schütz, John C. Waterton, Gerry Kenna on behalf of the TRISTAN Consortium

ISMRM 2023

Abstract

In normal hepatic function, toxins are absorbed and consequently excreted by the liver. As a liver-specific contrast agent which is actively taken up by the hepatocytes of the liver, gadoxetate dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) combined with tracer-kinetic (TK) modelling has the potential to be a useful tool for assessing hepatic transporter-mediated drug injury in animals and humans in vivo. However, in small animal studies, the ratio of main vessel diameter to scanning resolution is small, making it difficult to reliably measure the plasma arterial input function (AIF), cp(t). Signal data acquired from spleen ROIs are therefore typically used as a substitute, though these can also be unreliable. The aim of this study was to investigate the accuracy of modelling gadoxetate signals in rat liver when using signal data acquired from individual spleen ROIs as AIF and compare this with two alternatives, i.e., using 1) pooled spleen data as AIF, and 2) a standardised AIF derived from a simplified, two-compartment model of the rat circulation (hereafter referred to as the fixed model AIF).

AIF for tracer kinetic modelling

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