DOI: 10.5281/zenodo.15301607
title: TRISTAN gadoxetate kinetics

description: Database

Summary

Signal versus time curves measured with gadoxetate-enhanced MRI in the liver, with and without drugs.

Subjects

Human healthy volunteers, patients and rats.

Background

The data are taken from a series of preclinical and clinical studies performed by the TRISTAN project, in the period 2018-2024. The aim of these studies was to test if the effect of drugs on uptake and excretory function of the liver can be measured reliably with dynamic gadoxetate-enhanced MRI. Combined these studies provide proof of concept for a new MRI-based biomarker to predict the risk of liver-mediated drug-drug interactions, and of drug-induced liver injury. 

The data have been used to support a submission to the FDA's biomarker qualification program (details).

Format

All data are in dmr format - a folder with three csv files:



data.csv: Data dictionary

rois.csv: ROI curves

pars.csv: Subject parameters


The data can be read and manipulated interactively with common applications such as excel, or programmatically with the python package pydmr. 

Example usage



Rats multiple dosing: https://dcmri.org/examples/liver/plot_tristan_mdosing.html

Rat six test drugs: https://dcmri.org/examples/liver/plot_tristan6drugs.html

Rat reproducibility: https://dcmri.org/examples/liver/plot_tristan_repro.html

Healthy volunteers: https://dcmri.org/examples/liver/plot_tristan_volunteers_2scan.html

Patients: https://dcmri.org/examples/liver/plot_tristan_patients.html 


Version history



v0.0.1



Removed duplicate human results and combined all controls without treatment in a single file

Unique naming of subject ID's by adding a study acronym to the subject number: LDS for Leeds subjects, SHF for Sheffield subjects and GOT for Gothenburg subjects



v0.0.0



Combined various formats of previous studies in a coherent dmr format




Datasets

tristan_humans_healthy_rifampicin

The data were acquired in the aorta and liver of 8 healthy volunteers with dynamic gadoxetate-enhanced MRI, before and after administration of a drug (rifampicin) which is known to inhibit liver function. The assessments were done on two separate visits at least 2 weeks apart. On each visit, the volunteer had two scans each with a separate contrast agent injection of a quarter dose each. the scans were separated by a gap of about 1 hour to enable gadoxetate to clear from the liver. This design was deemed necessary for reliable measurement of excretion rate when liver function was inhibited.

The research question was to what extent rifampicin inhibits gadoxetate uptake rate from the extracellular space into the liver hepatocytes (khe, mL/min/100mL) and excretion rate from hepatocytes to bile (kbh, mL/100mL/min). 2 of the volunteers only had the baseline assessment, the other 8 volunteers completed the full study. The results showed consistent and strong inhibition of khe (95%) and kbh (40%) by rifampicin. This implies that rifampicin poses a risk of drug-drug interactions (DDI), meaning it can cause another drug to circulate in the body for far longer than expected, potentially causing harm or raising a need for dose adjustment.



 

The following data are available for each subject (see data.csv for more detail):





time_1: acquisition times of the first scan

time_2: acquisition times of the second scan

aorta_1: aorta signals in the first scan

aorta_2: aorta signals in the second scan

liver_1: liver signals in the first scan

liver_2: liver signals in the second scan

aorta_1_accept: valid aorta signals in the first scan

aorta_2_accept: valid aorta signals in the second scan

liver_1_accept: valid liver signals in the first scan

liver_2_accept: valid liver signals in the second scan

weight: subject weight in kg.

dose_1: contrast agent doses of first scan in mL/kg.

dose_2: contrast agent doses of second scan in mL/kg.

rate: contrast agent injection rate in mL/sec.

FA_1: Flip angle in degrees of the first scan

FA_2: Flip angle in degrees of the second scan

TR: repetition time in sec

t0: baseline length

T1_aorta_1: precontrast T1 of blood

T1_aorta_2: T1 of blood after 1st dynamic

T1_aorta_3: T1 of blood at the start of the 2nd scan

T1_liver_1: precontrast T1 of the liver

T1_liver_2: T1 of the liver after 1st dynamic

T1_liver_3: T1 of the liver at the start of the 2nd scan

liver_volume: liver volume in mL.





Please reference the following abstract when using these data (manuscript in preparation):


Thazin Min, Marta Tibiletti, Paul Hockings, Aleksandra Galetin, Ebony Gunwhy, Gerry Kenna, Nicola Melillo, Geoff JM Parker, Gunnar Schuetz, Daniel Scotcher, John Waterton, Ian Rowe, and Steven Sourbron. Measurement of liver function with dynamic gadoxetate-enhanced MRI: a validation study in healthy volunteers. Proc Intl Soc Mag Reson Med, Singapore 2024.


tristan_humans_healthy_metformin

 

Data from a similar experiment as the rifampicin study in healthy volunteers, but with the drug metformin and performed in another center with a different scanner vendor. The study includes 6 volunteers.

 

The variables are the same as in the rifampicin study.

 



Manuscript in preparation.


 



tristan_humans_healthy_ciclosporin

 

Data from a similar experiment as the metformin study in healthy volunteers, but with the drug ciclosporin. 

 

The variables are the same as in the rifampicin study.

 



Manuscript in preparation.


 



tristan_humans_healthy_controls

 

Five subjects enrolled in the rifampicin, metformin and ciclosporin studies had their baseline assessment but did not go on to have the the treatment visit, for various reasons. These data are combined together in this file. They can be added to the baseline data of the other studies to form a control cohort.




tristan_humans_patients_rifampicin

 
The study aimed to demonstrates the effect of rifampicin on liver function of patients with impaired function.

 

The data were acquired in the aorta and liver in 3 patients with dynamic gadoxetate-enhanced MRI. The study participants take rifampicin as part of their routine clinical workup, with an aim to promote their liver function. For this study, they were taken off rifampicin 3 days before the first scan, and placed back on rifampicin 3 days before the second scan. The aim was to determine the effect if rifampicin in uptake and excretion function of the liver.

The data confirmed that patients had significantly reduced uptake and excretion function in the absence of rifampicin. Rifampicin administration improved their excretory function but had no effect on their uptake function.

 

The variables are the same as in the rifampicin study in healthy volunteers, but the patient study was performed in a different center.

 

Manuscript in preparation.

 



tristan_rats_healthy_six_drugs

 
The study presented here measured gadoxetate uptake and excretion in healthy rats before and after injection of 6 test drugs (up to 6 rats per drug). Studies were performed in preclinical MRI scanners at 3 different centers and 2 different field strengths.



 

Results demonstrated that two of the tested drugs (rifampicin and cyclosporine) showed strong inhibition of both uptake and excretion. One drug (ketoconazole) inhibited uptake but not excretion. Three drugs (pioglitazone, bosentan and asunaprevir) inhibited excretion but not uptake.


The following data are available for each subject (see data.csv for more detail):



time: array of time points in sec

spleen: array of spleen signals in arbitrary units

liver: array of liver signals in arbitrary units.

FA: Flip angle in degrees

TR: repetition time in sec

n0: number of precontrast acquisitions

study: an integer identifying the substudy the scan was taken in

subject: a study-specific identifier of the subject in the range 1-6.

visit: either 1 (baseline) or 2 (drug or vehicle/saline).

center: center wehere the study was performed, either E, G or D.

field_strength: B0-field of scanner on whuch the study was performed

substance: what was injected, eg. saline, vehicle or drug name.

BAT: Bolus arrival time

duration: duration on the injection in sec.

Please reference the following paper when using these data:



Melillo N, Scotcher D, Kenna JG, Green C, Hines CDG, Laitinen I, Hockings PD, Ogungbenro K, Gunwhy ER, Sourbron S, et al. Use of In Vivo Imaging and Physiologically-Based Kinetic Modelling to Predict Hepatic Transporter Mediated Drug–Drug Interactions in Rats. Pharmaceutics. 2023; 15(3):896.
tristan_rats_healthy_reproducibility

Data from a study that aimed to determine the repreducibility and repeatability of gadoxetate uptake and excretion measurements in healthy rats. Data were acquired in different centers and field strengths to identify contributing factors. Some of the studies involved repeat scans in the same subject. In some studies data on the second day were taken after adminstration of a drug (rifampicin) to test if effect sizes were reproducible.

 
Available data for each subject are the same as in the six drugs study (see data.csv for more detail)

Please reference the following paper when using these data:



 

Ebony R. Gunwhy, Catherine D. G. Hines, Claudia Green, Iina Laitinen, Sirisha Tadimalla, Paul D. Hockings, Gunnar Schütz, J. Gerry Kenna, Steven Sourbron, and John C. Waterton. Assessment of hepatic transporter function in rats using dynamic gadoxetate-enhanced MRI: A reproducibility study. MAGMA. 2024 Aug;37(4):697-708. doi: 10.1007/s10334-024-01192-5. 
tristan_rats_healthy_multiple_dosing

 

These data are taken from a preclinical study which aimed to investigate the potential of gadoxetate-enhanced DCE-MRI to study acute inhibition of hepatocyte transporters of drug-induced liver injury (DILI) causing drugs, and to study potential changes in transporter function after chronic dosing.




Available data for each subject are the same as in the six drugs study (see data.csv for more detail)

Please reference the following abstract when using these data (manuscript in preparation):



Mikael Montelius, Steven Sourbron, Nicola Melillo, Daniel Scotcher, Aleksandra Galetin, Gunnar Schuetz, Claudia Green, Edvin Johansson, John C. Waterton, and Paul Hockings. Acute and chronic rifampicin effect on gadoxetate uptake in rats using gadoxetate DCE-MRI. Int Soc Mag Reson Med 2021; 2674.