Traditionally, hepatotoxicity and drug-induced liver injury (commonly abbreviated to DILI) have been difficult to predict using animal based preclinical testing. Often this leads to late stage failures during clinical development and, in certain circumstances, can even result in withdrawals following market approvals. In fact, hepatotoxicity is one of the most common reasons for late stage drug failure. So why is the liver such a common target for adverse effects and why is DILI so difficult to predict compared to other organ based effects?
Well, there are several reasons as detailed below;
- The liver is the main drug metabolising organ in the body. This is relevant if either the metabolites formed locally in the liver are toxic or if the patient is being co-administered medication which can interact with the drug through metabolism-mediated effects resulting in drug-drug interactions.
- When a drug is absorbed through the GI tract, it passes through the portal vein to the liver in a process known as first pass metabolism. As a consequence, exposure of the drug in the liver is elevated compared to the systemic circulation.
- The liver contains uptake and efflux transporters, both in the sinusoidal membrane as well as the bile duct, which can influence concentrations in the liver and can be another target for drug-drug interactions.
- Considerable inter-individual variability can occur between humans in drug metabolising enzyme and transporter expression. Disease and underlying conditions may also influence susceptibility to toxicity. Both of these factors can lead to a phenomenon known as idiosyncratic toxicity where the adverse effect only occurs in a small percentage of individuals, is not dose dependent and is difficult to predict.
- Animals have very different physiology to humans. Drug metabolism and transporter expression can differ considerably. Furthermore, preclinical animal toxicity testing typically doesn’t evaluate the impact of drug-drug interactions.
So how can we address these issues? Firstly, understanding the key metabolites formed between different species is an important step during drug development along with assessment of potential drug-drug interactions. Both of these evaluations are requirements for IND and/or NDA approval. Secondly, supplementing the mandatory preclinical animal testing with human cell-based assays may assist in identifying potential hepatotoxic events before the compound reaches the clinic.
Knowledge of the mechanisms behind hepatotoxicity and DILI is growing. Reactive metabolite formation, oxidative stress and mitochondrial dysfunction are common mechanisms along with canalicular transporter-mediated effects resulting in cholestasis. All of these mechanisms can now be evaluated using in vitro human cell-based models. Recent studies have also demonstrated the benefits of using 3D cell-based for evaluating hepatotoxicity.
At SOT in Baltimore from 12-16th March 2017, Cyprotex presented research in the field of 3D cell-based models for predicting hepatotoxicity. The study evaluated co-culture models using primary human hepatocytes in combination with human non-parenchymal cells. It studied donor-related effects, CYP activity over time, DILI prediction as well as normalisation to tissue specific Cmax levels.
To learn more about the advantages of using 3D cell-based models, download our poster.