Liver T1 Mapping with vFA

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Bias, repeatability and reproducibility of liver T1 mapping with variable flip angles

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Liver T1 Mapping with vFA

Bias, repeatability and reproducibility of liver T1 mapping with variable flip angles

Sirisha Tadimalla, Daniel Wilson, David Shelley, Gavin Bainbridge, Margaret Saysell, Iosif A Mendichovszky, Martin Graves, Geoff JM Parker, Steven Sourbron


ISMRM Conference 2021

Abstract

A multi-centre, multi-vendor study in 8 travelling healthy volunteers was conducted for technical validation of variable flip angle (VFA) T1 mapping in the liver across 6 scanners (3 vendors and 2 field strengths). The 95% CI was 28 ± 8% for the bias in liver T1, 10 ± 3% for the intra-scanner repeatability CV and 28 ± 6% for the inter-scanner reproducibility CV. These values are comparable to literature values for B1+-corrected VFA T1 in prostate, brain, breast, and phantoms. Any proposed refinement of the VFA method in the liver should demonstrate a significant improvement on those benchmarks before it can be recommended as a future standard.

Liver T1 Mapping with vFA
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Gadoxetate MRI to assess rifampicin effect

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Acute and chronic rifampicin effect on gadoxetate uptake in rats using gadoxetate DCE-MRI

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Gadoxetate MRI to assess rifampicin effect

Acute and chronic rifampicin effect on gadoxetate uptake in rats using gadoxetate DCE-MRI

Mikael Montelius, Steven Sourbron, Nicola Melillo, Daniel Scotcher, Aleksandra Galetin, Gunnar Schuetz, Claudia Green, Edvin Johansson, John Waterton, Paul D. Hockings


ISMRM Conference 2021

Abstract

Non-invasive biomarkers for Drug Induced Liver Injury, which cause liver failure and impede drug development, and Drug-Drug Interactions affecting pharmacokinetics of drugs when combined are needed. We used gadoxetate DCE-MRI to measure clinical and high dose rifampicin effects on hepatocellular uptake in acute and chronic settings in rats. At high dose, uptake was significantly reduced after acute dosing, and returned to baseline after chronic dosing. Similar but non-significant effects was seen at clinical dose levels. We thus demonstrated the potential of gadoxetate DCE-MRI to non-invasively assess drug-induced inhibition of hepatocellular transport and DDIs. 
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Gadoxetate MRI to assess rifampicin effect
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Assess Liver Transporter Kinetics and DDI from Imaging Data

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Insights on hepatobiliary transporter kinetics and DDIs from tissue imaging data: Lessons from PBPK modelling of gadoxetate

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Assess Liver Transporter Kinetics and DDI from Imaging Data

Insights on hepatobiliary transporter kinetics and DDIs from tissue imaging data: Lessons from PBPK modelling of gadoxetate

Daniel Scotcher

2021 Drug Metabolism Discussion Group and Swedish Academy of Pharmaceutical Sciences Online Joint Meeting

Abstract

Physiologically-based pharmacokinetic (PBPK) modelling provides a framework for in vitro-in vivo extrapolation (IVIVE) of drug disposition. Quantitative prediction of transporter-mediated processes and tissue permeation remains challenging due to the lack of available in vivo tissue data for model validation. Gadoxetate is a magnetic resonance imaging (MRI) contrast agent and 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. The in vitro uptake kinetics of gadoxetate in plated rat hepatocytes were assessed, and transporter kinetic parameters derived using a mechanistic cell model. 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 and absence of a single 10 mg/kg intravenous dose of rifampicin were used for PBPK model refinement. The PBPK model successfully predicted gadoxetate concentrations in systemic blood and spleen and corresponding increase in gadoxetate systemic exposure in the presence of rifampicin, whereas 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. The current study demonstrates utility of tissue imaging data in validating and refining PBPK models for prediction of transporter-mediated disposition.
 

Assess Liver Transporter Kinetics and DDI from Imaging Data
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Imaging of DDI risk with liver transporters

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In vivo imaging and evaluation of drug-drug interaction risk arising via hepatobiliary transporters

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Imaging of DDI risk with liver transporters

In vivo imaging and evaluation of drug-drug interaction risk arising via hepatobiliary transporters

J. Gerry Kenna, Claudia Green, Catherine D. G. Hines Iina Laitinen, Aleksandra Galetin, Paul D. Hockings,  Nicola Melillo, Mikael Montelius,  Daniel Scotcher, Steven Sourbron, John C. Watertone, Gunnar Schütz
 

Virtual 2021 Annual Meeting of the US Society of Toxicology and ToxExpo

Abstract

Inhibition of transporters that mediate hepatic drug uptake and/or biliary excretion may cause clinically relevant drug-drug interactions (DDIs) leading to potentiated or reduced efficacy, and/or increased or reduced toxicity to liver or other tissues. These DDIs are difficult to assess, since accurate prediction of changes in tissue exposure in vivo based on in vitro transport interaction data is challenging. Dynamic contract enhanced magnetic resonance imaging (DCE-MRI) enables in vivo visualisation of hepatic transporter mediated uptake and efflux of the contrast agent gadoxetate. When analysed using a compartmental kinetic model of gadoxetate disposition, gadoxetate DCE-MRI studies provide quantitative rate constants for hepatic gadoxetate uptake (khe) and biliary excretion (kbh). These processes are mediated primarily by Organic Anion Transport Polypeptides (OATPs) and Multidrug Resistance Protein Type 2 (MRP2), respectively. To evaluate drug effects on hepatic gadoxetate khe and kbh, DCE-MRI studies were undertaken in adult male Wistar rats (approx. 250g body weight) dosed intravenously (iv) with single doses of 
drugs (rifampicin, asunaprevir, bosentan, cyclosporin, ketoconazole, pioglitazone) that inhibited rat oatp, and human OATP, activities in vitro. Drug doses were selected, via pharmacokinetic modelling and simulation, to achieve rat peripheral blood plasma concentrations following iv administration that were equivalent to steady-state human blood plasma concentrations. Simulations predicted that the selected doses of rifampicin and cyclosporin reduced liver gadoxetate exposure in vivo, whereas the other tested drugs did not. Gadoxetate khe values were determined 20 min after iv administration of dose vehicle and then, in the same animals, after a minimum 48 hr washout interval and following drug administration (n=6 per group). Gadoxetate khe (min-1) was reduced (p < 0.01) following administration of rifampicin at 2 mg/kg (mean +SD, dose: 0.44+0.06; vehicle: 0.92+0.17) or cyclosporin at 5 mg/kg (mean+SD, dose: 0.08+0.02; vehicle: 1.00+0.24); but not after dosing of asunaprevir at 5 mg/kg, bosentan at 2 mg/kg, ketoconazole at 3 mg/kg or pioglitazone at 0.4 mg/kg. These results indicate that gadoxetate DCE-MRI may aid assessment of hepatic transporter-mediated DDI risk.

Imaging of DDI risk with liver transporters
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Proton relaxation in liver

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Survey of Water Proton Longitudinal Relaxation in Liver in vivo

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Liver longitudinal relaxation in-vivo

Survey of water proton longitudinal relaxation in liver in vivo

by John Charles Waterton


Magn Reson Mater Phy (2021). doi: 10.1007/s10334-021-00928-x

Abstract

Objective: To determine the variability, and preferred values, for normal liver longitudinal water proton relaxation rate R1 in the published literature.

Methods: Values of mean R1 and between-subject variance were obtained from literature searching. Weighted means were fitted to a heuristic and to a model.

Results: After exclusions, 116 publications (143 studies) remained, representing apparently normal liver in 3392 humans, 99 mice and 249 rats. Seventeen field strengths were included between 0.04 T and 9.4 T. Older studies tended to report higher between-subject coefficients of variation (CoV), but for studies published since 1992, the median between-subject CoV was 7.4%, and in half of those studies, measured R1 deviated from model by 8.0% or less.

Discussion: The within-study between-subject CoV incorporates repeatability error and true between-subject variation. Between-study variation also incorporates between-population variation, together with bias from interactions between methodology and physiology. While quantitative relaxometry ultimately requires validation with phantoms and analysis of propagation of errors, this survey allows investigators to compare their own R1 and variability values with the range of existing literature.

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LIVER LONGITUDINAL RELAXATION IN VIVO
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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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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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