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.

By testing your lead candidates against our human liver-on-chip model, the risk of an unexpected late-stage surprise is reduced. Our long term and multifunctional liver culture is compatible with a wide variety of different drug modalities. It is suitable for the mono or co-culturing of human (or animal) cells and can be utilized for a variety of single and multi-organ ADME applications.

With high metabolic activity and cellular functions maintained for at least 4 weeks, our liver-on-a-chip combined with LC-MS analysis enable the generation of temporal (repeat sampling) metabolite profiles capturing phase I and II metabolism. It is also possible to differentiate and quantify a wide range of compound clearance rates, including slowly metabolised drugs.

The performance of our Liver-on-a-chip significantly out-performs the drug metabolism capabilities of equivalent cells plated in 2D, and predicted clearance rates for a range of well-known drugs tested show good agreement with in vivo clinical data (Tsamandouras et al., 2017).

Furthermore, direct correlations between metabolite formation and liver toxicity can be derived from the same sample using cell health measurements to flag any potential adverse effects whilst multi-organ studies offer the ability to more accurately determine bioavailability by linking the liver to a barrier model to evaluate drug absorption and metabolism within one interconnected system.

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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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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