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Translation from rat to human
Translation from rat to human: issues and current status
by Steven Sourbron
HTN Meeting 2022
The TRISTAN project has current completed all preclinical technical and biological validation work, and has started the process of translating methods from rats to humans. While similar methods exist and have been deployed in other liver applications, the particular focus on DILI and DDI’s poses technical constraints that require new solutions. In particular, the aim to characterize uptake rates of Gadoxetate into cells as well as the slow excretion from cells into bile requires long acquisitions – especially in the presence of strongly inhibited uptake and excretion. The aim of this talk is to sketch out the trajectory of clinical translation in TRISTAN so far and present detail on challenges encountered.
One issue in human quantitative MRI in general is the large heterogeneity of clinical scanners by multiple vendors, the lack of standardisation in hardware and software and the fact that these are devices optimized for qualitative rather than quantitative imaging. This is in contrast to preclinical MRI scanners which are scientific instruments by definition and at higher fields are currently supplied by one single vendor. In order to estimate and help understand the impact of this scanner heterogeneity under real-world conditions of today, the first step towards clinical translation was a multi-vendor multi-site repeatability and reproducibility study of quantitative MRI in the absence of Gadoxetate [Tadimalla et al JMRI 2022]. The methodology, results and conclusions of this study will be reviewed briefly, as well as the practical experience of running them.
The second stage towards clinical translation of the assay is an experimental medicine study in healthy volunteers, aiming to (1) derive benchmark values for Gadoxetate uptake and extraction under normal conditions and in the presence of a strong inhibitor (rifampicin), and (2) demonstrate that the effect of a strong inhibitor can be characterized reliably and consistently across subjects. Because these are the first Gadoxetate-enhanced dynamic data in humans, the study has an adaptive design allowing in the initial stages for modifications in the methodology should the data indicate the need to do so. Initially the dose of Gadoxetate for these studies is chosen at the lowest feasible value, and the study design allows this too to be stepped up if noise levels are deemed too high for reliable quantification. In this second part of the talk, I will present our first experience with the adaptive stage of the study, showing methodology and results in 3 volunteers with and without rifampicin.
We will conclude the talk with an outlook on clinical studies that are planned in the next stage of the development.