Standard in vitro DMPK studies face many challenges, including: incompatibility with new therapeutic modalities, inaccurate predictions of human in vivo clearance rates (particularly for low clearance compounds), and missing rare or human specific metabolites. The latter can and does put clinical programs on hold.

By testing your lead candidates against our human liver-on-chip model, the the risk of an unexpected surprise is reduced. Compatible with a wide variety of different drug modalities our cultures produce a range of phase I and II human drug metabolites at different rates. These can be identified in temporal (repeat sampling) studies using LCMS analysis. Furthermore, cell health measurements can be made from the same sample, enabling direct correlations between metabolite formation and toxicity to be extrapolated.

With high metabolic activity maintained for weeks, it is also possible to differentiate and quantify a wide range of clearance rates, including slowly metabolised drugs.

Detecting compounds with varying clearance rates – clearance of disopyramide (yellow) , diclofenac (pink) and phenacetin (green) in LC12 plates

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Predicting human hepatic clearance – comparison of in vivo and liver-on-chip hepatic clearance rates of five common molecules

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With safety concerns being the principal cause for failures in phases 1 and 2 of clinical trials, it is clear that we need more predictive models within drug discovery and development to improve translatability. Focus has turned to human in vitro 3D liver models to provide the solution.

To understand causality and mechanistic aspects of drug-induced liver toxicity in great detail, take a step beyond what is currently possible and submit your lead candidates for test against our human liver-on-chip in vitro model.

Maintained under flow perfusion for up to 4 weeks, co-cultures of human hepatocyte and non-parenchymal cells (NPC) form highly functional 3D liver microtissues. Following acute or chronic drug dosing, an almost exponential number of functional liver-specific endpoints can be analysed from the culture medium, liver microtissue, or via non-invasive techniques from which distinct mechanistic “signatures” of hepatotoxicity can be observed. End points include clinical markers that are notoriously difficult to detect in vitro (e.g. AST/ALT).

More complex mechanistic questions can be investigated, using our liver-on-chip model, such as the stratification of different patient populations versus their DILI susceptibility and toxicity profiles, or inflammatory-mediated toxicity. It is even possible to study inter-organ crosstalk and toxicity through use of multi-organ microphysiological systems such as gut-liver, lung-liver or circulating immune cells and liver.

Detecting human specific toxicant signatures – hierarchical cluster analysis of LDH leakage, albumin secretion and Urea production to assess toxicity of compounds

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 Investigating causality – detecting cholestatic injury following treatment with hepatotoxicant

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