Altogether, this has led to the proposal that the better the quality of non-clinical safety profiles, the higher the success rates for moving phase II upward ( Cook et al., 2014 Walker et al., 2020). Within DILI, the idiosyncratic category is particularly difficult to identify by the pharmaceutical industry as it is almost undetectable in animal models ( Kuna et al., 2018 Walker et al., 2020). Moreover, drug-induced liver injury (DILI) is a rare, but potentially fatal event, resultant from the poor translation between clinical trials and clinical practice and highlights the importance of targeting population variability at non-clinical stages ( Jones et al., 2018). One of the reasons for this discrepancy is the differential expression and activity of drug metabolizing enzymes between animals and humans that might confound the extrapolation of data derived from non-clinical species ( Martignoni et al., 2006 Ruoß et al., 2020).
Indeed, besides raising ethical issues, animal models often fail to correlate with human toxicity, since several toxic features disclosed in human trials were not predicted by animal studies ( Olson et al., 2000 Shanks et al., 2009). Importantly, about 40–50% of the drug candidates associated with hepatotoxicity in humans did not present the same toxicological concern in animal models ( van Tonder et al., 2013). Approximately 18–30% of such withdrawals are caused by hepatotoxic effects, showing that the liver is the most frequent organ for adverse drug reactions (ADRs) ( Onakpoya et al., 2016 Siramshetty et al., 2016 Zhang X. Even after reaching the market (phase IV), there is still a relevant number of drug withdrawals for toxicological reasons. This is mostly due to lack of drug efficacy or safety issues that occur essentially in the clinical phases IIb and III of drug development ( Kola and Landis, 2004 Paul et al., 2010). It is a process that usually takes 10–15 years, with a success rate from phase I to launch of less than 10% ( Dowden and Munro, 2019). (2020), the median investment of bringing a new drug into the market, also accounting for failed trials, was estimated at $985.3 million over the period of 2009–2018. According to a recent study by Wouters et al. The process of development of new drugs is a costly investment with the pharmaceutical industry facing considerable challenges regarding the balance between the political pressure to increase drugs safety while reducing the cost of medicines. Finally, taking a step forward, we propose a roadmap for the assessment of drugs hepatotoxicity based on fully characterized fit-for-purpose in vitro models, taking advantage of the best of each model, which will ultimately contribute to more informed decision-making in the drug development and risk assessment fields. In addition, since toxic responses are greatly dependent on the culture model, a comparative analysis of the toxicity studies performed using two-dimensional (2D) and 3D in vitro strategies with recognized hepatotoxic compounds, such as paracetamol, diclofenac, and troglitazone is performed, further highlighting the need for harmonization of the respective characterization methods. This comprehensive review addresses the drug-induced hepatotoxicity mechanisms and the currently available 3D liver in vitro models, their characteristics, as well as their advantages and limitations for human hepatotoxicity assessment. Three-dimensional (3D) or microfluidic technologies allow to better recapitulate hepatocyte organization and cell-matrix contacts, to include additional cell types, to incorporate fluid flow and to create gradients of oxygen and nutrients, which have led to improved differentiated cell phenotype and functionality.
In an effort to increase the prediction of human hepatotoxicity, different approaches to enhance the physiological relevance of hepatic in vitro systems are being pursued. This is in part caused by animal models that fail to predict various human adverse drug reactions (ADRs), resulting in undetected hepatotoxicity at the non-clinical phase of drug development. The poor predictability of human liver toxicity is still causing high attrition rates of drug candidates in the pharmaceutical industry at the non-clinical, clinical, and post-marketing authorization stages. 2Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB, Stuttgart, Germany.1Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.Rodrigues 1†, Madalena Cipriano 2†, Armanda V.
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