Cyprotex are delighted to have published a review article in the Archives of Toxicology this month entitled ‘The Evolution of Strategies to Minimise the Risk of Human Drug-Induced Liver Injury (DILI) in Drug Discovery and Development’. This article charts a course through the key developments in DILI liability strategy within the pharmaceutical industry, as well as delving into recent approaches developed by our own team of scientists here at Cyprotex. The importance of considering drug exposure to contextualise in vitro assay data and the key role played by some hepatic drug transporters are highlighted.
DILI remains the primary cause for drug failure during clinical trials, with approximately 18% of compound withdrawals over the last 60 years being due to hepatotoxicity alone. This can be attributed to the poor translation between historical animal models and human clinical outcome. In response to this, the pharmaceutical industry has been instrumental in driving the further development of more sophisticated human-focussed predictive in vitro assay systems. These systems also incorporate multi-parametric endpoints to address the challenges of early stage drug discovery failures due to hepatotoxicity in a more comprehensive, mechanistic manner. A particular example of this paradigm change can be seen in the movement from single-cell 2D in vitro models to more advanced 3D systems which have been developed with a vision to reflect better the characteristics and behaviours of human tissues in vivo.
To address the complexities of DILI strategy, the review considers how to approach the challenge of using data from existing publications as a basis for establishing a definitive approach. There is a high degree of inconsistency observed in how current publications deal with the assignment of different DILI categories; furthermore, there is no single approach to the selection of reference compounds and the question remains as to how many compounds are sufficient to evaluate the different DILI strategies available.
By examining and assessing the recent DILI strategies developed in the pharmaceutical industry, a number of distinct challenges have emerged that need to be overcome before a definitive approach can begin to be considered. However, efforts are being made to improve upon standardisation, as in the Liver Toxicity Knowledge Base (LTKB) initiated by the US Food and Drug Administration (FDA). In addition, 3D models are demonstrating promising early DILI prediction accuracy, and combining this with multi-parametric approaches, such as High Content Imaging (HCI) and transcriptomic analysis developed at Cyprotex, will ultimately improve our mechanistic understanding and de-risking of DILI.
To read the full review article, click here.
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