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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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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Accuracy, repeatability, and reproducibility of R1

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Accuracy, repeatability, and reproducibility of R1 in 12 small-animal MRI systems (Conference Abstract)

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Conference Abstract: Phantom R1 Repeabililty

Accuracy, repeatability, and reproducibility of R1 in 12 small-animal MRI systems (Conference Abstract)

JC Waterton, CDG Hines, PD Hockings, I Laitinen, S Ziemian, S Campbell, M Gottschalk, C Green, M Haase, K Hoffmann, H-P Juretschke, S Koehler, W Lloyd, Y Luo, I Mahmutovic Persson, JPB O Connor, LE Olsson, GJM Parker, K Pindoriah, JE Schneider, D Steinmann, K Strobel, I Teh, A Veltien, X Zhang, G Schuetz


British Chapter ISMRM Annual Meeting 24th-26th September 2018, Oxford, UK Poster Abstract PO-19


Background:  Many translational MR biomarkers derive from measurements of the longitudinal relaxation rate R1, but evidence for between-site reproducibility of R1 in small-animal MRI is lacking.  Objective: To assess R1 repeatability and multi-site reproducibility in phantoms for preclinical MRI. Methods: R1 was measured by saturation recovery in 2% agarose phantoms with five nickel chloride concentrations in 12 magnets at 5 field strengths in 11 centres on two different occasions within 1-13 days.  R1 was analysed in three different regions of interest, giving 360 measurements in total.  Root-mean-square repeatability and reproducibility coefficients of variation were calculated.  Relaxivities were calculated.  Results: Day-to-day repeatability (N=180 regions of interest) was 2.3%.  Between-centre reproducibility (N=9 centres) was 1.4%.  The relaxivity of aqueous Ni2+ in 2% agarose varied between 0.66 s-1mM-1 at 3T and 0.94 s-1mM-1 at 11.7T.

CONFERENCE ABSTRACT: PHANTOM R1 REPEABILILTY
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Accuracy, repeatability, and reproducibility of R1 in 12

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Accuracy, repeatability, and reproducibility of R1 in 12 small-animal MRI systems (Conference Abstract)

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Conference Abstract: Accuracy of R1 determination

Accuracy, repeatability, and reproducibility of R1 in 12 small-animal MRI systems (Conference Abstract)

Waterton JC, Hines CDG, Hockings PD, Laitinen I, Ziemian S, Campbell S, Gottschalk M, Green C, Haase M, Hoffmann K, Juretschke H-P, Koehler S, Lloyd W, Y Luo Y, Mahmutovic Persson I, O’Connor JPB, Olsson LE, Parker GJM, Pindoria K, Schneider JE, Steinmann D, Strobel K, Teh I, Veltien A, Zhang X, Schütz G


Proceedings of the International Society of Magnetic Resonance in Medicine 27th Scientific Meeting and Exhibition, Montréal, Canada 11th-16th May 2019

 

CONFERENCE ABSTRACT: ACCURACY OF R1 DETERMINATION
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Inter-site repeatability and quantitative assessment

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Inter-site repeatability and quantitative assessment of hepatic transporter function with DCE-MRI in rats (Conference Abstract)

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Conference Abstract: Repeatability of liver transporter function assessment

Inter-site repeatability and quantitative assessment of hepatic transporter function with DCE-MRI in rats (Conference Abstract)

Claudia Green, Sirisha Tadimalla, Denise Steinmann, Steven Sourbron, Sascha Koehler, Hans-Paul Juretschke, Iina Laitinen, John C. Waterton, Paul D. Hockings, Catherine D. G. Hines, Gunnar Schütz


Proceedings of the International Society of Magnetic Resonance in Medicine 27th Scientific Meeting and Exhibition, Montréal, Canada 11th-16th May 2019

CONFERENCE ABSTRACT: REPEATABILITY OF LIVER TRANSPORTER FUNCTION ASSESSMENT
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Repeatability and reproducibility of longitudinal relaxation rate

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Repeatability and reproducibility of longitudinal relaxation rate in 12 small-animal MRI systems

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R1 repeatability and reproducibility for animal MRI

Repeatability and reproducibility of longitudinal relaxation rate in 12 small-animal MRI systems

Waterton JC, Hines CDG, Hockings PD, Laitinen I, Ziemian S, Campbell S, Gottschalk M, Green C, Haase M, Hoffmann K, Juretschke H-P, Koehler S, Lloyd W, Y Luo Y, Mahmutovic Persson I, O’Connor JPB, Olsson LE, Parker GJM, Pindoria K, Schneider JE, Steinmann D, Strobel K, Teh I, Veltien A, Zhang X, Schütz G


Magnetic Resonance Imaging, Volume 59, June 2019, Pages 121-129 doi:10.1016/j.mri.2019.03.008

 

Abstract

Background: Many translational MR biomarkers derive from measurements of the water proton longitudinal relaxation rate R1, but evidence for between-site reproducibility of R1 in small-animal MRI is lacking.

Objective: To assess R1 repeatability and multi-site reproducibility in phantoms for preclinical MRI.

Methods: R1 was measured by saturation recovery in 2% agarose phantoms with five nickel chloride concentrations in 12 magnets at 5 field strengths in 11 centres on two different occasions within 1-13 days. R1 was analysed in three different regions of interest, giving 360 measurements in total. Root-mean-square repeatability and reproducibility coefficients of variation (CoV) were calculated. Propagation of reproducibility errors into 21 translational MR measurements and biomarkers was estimated. Relaxivities were calculated. Dynamic signal stability was also measured.

Results: CoV for day-to-day repeatability (N=180 regions of interest) was 2.34% and for between-centre reproducibility (N=9 centres) was 1.43%. Mostly, these do not propagate to biologically significant between-centre error, although a few R1-based MR biomarkers were found to be quite sensitive even to such small errors in R1, notably in myocardial fibrosis, in white matter, and in oxygen-enhanced MRI. The relaxivity of aqueous Ni2+ in 2% agarose varied between 0.66 s-1mM-1 at 3T and 0.94 s-1mM-1 at 11.7T.

Interpretation: While several factors affect the reproducibility of R1-based MR biomarkers measured preclinically, between-centre propagation of errors arising from intrinsic equipment irreproducibility should in most cases be small. However, in a few specific cases special care in R1-accuracy is warranted.

R1 REPEATABILITY AND REPRODUCIBILITY FOR ANIMAL MRI
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Tracer kinetic modelling of dynamic Gadoxetate-enhanced MRI

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Tracer kinetic modelling of dynamic Gadoxetate-enhanced MRI (Conference Abstract)

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Conference Abstract: Kinetic modelling of Gadoxetate MRI

Tracer kinetic modelling of dynamic Gadoxetate-enhanced MRI (Conference Abstract)

Steven Sourbron


Hepatocyte Transporter Network Meeting, September 2019. HTNM 2019 Presentation.

CONFERENCE ABSTRACT: KINETIC MODELLING OF GADOXETATE MRI
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Clinical Gd-EOB-DTPA MRI to detect the inhibition

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Clinical Gd-EOB-DTPA MRI to detect the inhibition of hepatocyte transporters (Conference Abstract)

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Conference Abstract: Gadoxetate MRI to see liver transporter inhibition

Clinical Gd-EOB-DTPA MRI to detect the inhibition of hepatocyte transporters (Conference Abstract)

Sirisha Tadimalla


Hepatocyte Transporter Network Meeting, September 2019. HTNM 2019 Presentation.

CONFERENCE ABSTRACT: GADOXETATE MRI TO SEE LIVER TRANSPORTER INHIBITION
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Physiologically-based pharmacokinetic modelling of transporter

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Physiologically-based pharmacokinetic modelling of transporter-mediated hepatic disposition using the imaging biomarker gadoxetate (Conference Abstract)

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Conference Abstract: PBPK modelling of transporter-mediated hepatic disposition

Physiologically-based pharmacokinetic modelling of transporter-mediated hepatic disposition using the imaging biomarker gadoxetate (Conference Abstract)

Daniel Scotcher, Sirisha Tadimalla, Adam Darwich, Sabina Ziemian, Kayode Ogungbenro, Gunnar Schütz, Steven Sourbron, Aleksandra Galetin


ISSX conference 2019.

Abstract

Physiologically-based pharmacokinetic (PBPK) modelling provides a framework for in vitro-in vivo extrapolation (IVIVE) of drug disposition. However, prediction of transporter-mediated processes and tissue permeation remains challenging due to the lack of available in vivo tissue data for validation. Gadoxetate is a magnetic resonance imaging (MRI) contrast agent used clinically for hepatic lesion characterisation. As a substrate of organic anion transporting polypeptide 1B1 (OATP1B1) and multidrug resistance-associated protein 2 (MRP2), gadoxetate is being explored as a novel imaging biomarker for hepatic transporter function in context of evaluation of drug-drug interactions and drug induced liver injury [1]. The current study aimed to characterise uptake kinetics of gadoxetate in plated rat hepatocytes and develop a PBPK model to predict gadoxetate in vivo plasma and liver exposure. In vitro uptake was measured by incubating rat hepatocytes with 0.01 – 10mM gadoxetate for 0.5 – 150 min. Relevant in vitro transporter kinetic parameters were derived using a mechanistic cell model [2]. Subsequently, a novel PBPK model was developed for gadoxetate in rat, where liver uptake and cellular binding were informed by IVIVE. Gadoxetate in vivo blood, spleen and liver data obtained in the presence (n=9) and absence (n=27) of a single 10 mg/kg intravenous dose of rifampicin [3] were used for PBPK model validation/refinement. In vitro gadoxetate uptake affinity constant (Km) obtained in rat hepatocytes was 0.106 mM (n=4 rats), with saturable active transport accounting for 94% of gadoxetate cellular uptake; bidirectional transport, not saturable under current experimental conditions, was minor. The fraction unbound in hepatocytes was estimated to be 0.65. The total (Kp,u) and unbound (Kp,uu) hepatocyte:media partition coefficients were 26.0 and 16.9, respectively. The PBPK model successfully predicted gadoxetate concentrations in systemic blood and spleen and corresponding 2-fold increase in gadoxetate systemic exposure in the presence of rifampicin. In contrast, liver concentrations were under-predicted. Refinement of the PBPK model using the dynamic contrast agent enhanced (DCE)-MRI data enabled recovery of the liver profile, assuming complete and partial inhibition of hepatic uptake and biliary efflux by rifampicin, respectively. The current study demonstrates utility of imaging data in validating and refining PBPK models for prediction of transporter-mediated disposition; considerations of interpretation of quantitative DCE-MRI data to inform PBPK models are discussed.

CONFERENCE ABSTRACT: PBPK MODELLING OF TRANSPORTER-MEDIATED HEPATIC DISPOSITION
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