Accuracy, repeatability, and reproducibility of R1

Private
Public

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

  • 144

Publications
Take a look

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
Article categories

Accuracy, repeatability, and reproducibility of R1 in 12

Private
Public

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

  • 137

Publications
Take a look

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
Article categories

Inter-site repeatability and quantitative assessment

Private
Public

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

  • 136

Publications
Take a look

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
Article categories

Repeatability and reproducibility of longitudinal relaxation rate

Private
Public

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

  • 132

Publications
Take a look

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
Article categories

Tracer kinetic modelling of dynamic Gadoxetate-enhanced MRI

Private
Public

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

  • 126

Publications
Take a look

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
Article categories

Clinical Gd-EOB-DTPA MRI to detect the inhibition

Private
Public

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

  • 125

Publications
Take a look

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
Article categories

Physiologically-based pharmacokinetic modelling of transporter

Private
Public

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

  • 117

Publications
Take a look

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
Article categories

Ex vivo gadoxetate relaxivities in rat liver tissue and blood at five magnetic field strengths from 1.41 to 7 T

Private
Public

Ex vivo gadoxetate relaxivities in rat liver tissue and blood at five magnetic field strengths from 1.41 to 7 T

  • 113

Publications
Take a look

Gadoxetate Relaxivity in Different Liver Compartments

Ex vivo gadoxetate relaxivities in rat liver tissue and blood at five magnetic field strengths from 1.41 to 7 T

Sabina Ziemian, Claudia Green, Steven Sourbron, Gregor Jost, Gunnar Schütz, Catherine D.G. Hines


NMR in Biomedicine, 26 August 2020, e4401; doi:10.1002/nbm.4401

 

Abstract

Quantitative mapping of gadoxetate uptake and excretion rates in liver cells has shown potential to significantly improve the management of chronic liver disease and liver cancer. Unfortunately, technical and clinical validation of the technique is currently hampered by the lack of data on gadoxetate relaxivity. The aim of this study was to fill this gap by measuring gadoxetate relaxivity in liver tissue, which approximates hepatocytes, in blood, urine and bile at magnetic field strengths of 1.41, 1.5, 3, 4.7 and 7 T. Measurements were performed ex vivo in 44 female Mrp2 knockout rats and 30 female wild‐type rats who had received an intravenous bolus of either 10, 25 or 40 μmol/kg gadoxetate. T1 was measured at 37 ± 3°C on NMR instruments (1.41 and 3 T), small‐animal MRI (4.7 and 7 T) and clinical MRI (1.5 and 3 T). Gadolinium concentration was measured with optical emission spectrometry or mass spectrometry. The impact on measurements of gadoxetate rate constants was determined by generalizing pharmacokinetic models to tissues with different relaxivities. Relaxivity values (L mmol−1 s−1) showed the expected dependency on tissue/biofluid type and field strength, ranging from 15.0 ± 0.9 (1.41) to 6.0 ± 0.3 (7) T in liver tissue, from 7.5 ± 0.2 (1.41) to 6.2 ± 0.3 (7) T in blood, from 5.6 ± 0.1 (1.41) to 4.5 ± 0.1 (7) T in urine and from 5.6 ± 0.4 (1.41) to 4.3 ± 0.6 (7) T in bile. Failing to correct for the relaxivity difference between liver tissue and blood overestimates intracellular uptake rates by a factor of 2.0 at 1.41 T, 1.8 at 1.5 T, 1.5 at 3 T and 1.2 at 4.7 T. The relaxivity values derived in this study can be used retrospectively and prospectively to remove a well‐known bias in gadoxetate rate constants. This will promote the clinical translation of MR‐based liver function assessment by enabling direct validation against reference methods and a more effective translation between in vitro findings, animal models and patient studies.

GADOXETATE RELAXIVITY IN DIFFERENT LIVER COMPARTMENTS
Article categories
Subscribe to Liver