Minimizing DILI risk in drug discovery - A screening tool for drug candidates.

Drug-induced liver injury (DILI) is a leading cause of acute hepatic failure and a major reason for market withdrawal of drugs. Idiosyncratic DILI is multifactorial, with unclear dose-dependency and poor predictability since the underlying patient-related susceptibilities are not sufficiently understood. Because of these limitations, a pharmaceutical research option would be to reduce the compound-related risk factors in the drug-discovery process. Here we describe the development and validation of a methodology for the assessment of DILI risk of drug candidates. As a training set, 81 marketed or withdrawn compounds with differing DILI rates - according to the FDA categorization - were tested in a combination of assays covering different mechanisms and endpoints contributing to human DILI. These include the generation of reactive metabolites (CYP3A4 time-dependent inhibition and glutathione adduct formation), inhibition of the human bile salt export pump (BSEP), mitochondrial toxicity and cytotoxicity (fibroblasts and human hepatocytes). Different approaches for dose- and exposure-based calibrations were assessed and the same parameters applied to a test set of 39 different compounds. We achieved a similar performance to the training set with an overall accuracy of 79% correctly predicted, a sensitivity of 76% and a specificity of 82%. This test system may be applied in a prospective manner to reduce the risk of idiosyncratic DILI of drug candidates.

Disease severity declines over time after a wild boar population has been affected by classical swine fever--legend or actual epidemiological process?

Classical swine fever (CSF) is a severe multi-systemic disease that can affect both domestic pigs and wild boar. Past outbreaks in European wild boar involved high-virulent CSF virus (CSFV) strains and were mostly self-limiting. In these cases, morbidity and mortality rates were high in the affected regions. In contrast, endemic infections have been observed in several European wild boar populations in recent decades. Morbidity and mortality rates were much lower despite the fact that outbreaks were still detected via diseased or fallen animals. The virus strains involved were mostly classified as genotype 2.3 strains of moderate virulence causing age-dependent disease outcomes. The mechanisms leading to the establishment and perpetuation of endemicity are still not fully understood, but the factor "moderate virulence" seems to be of considerable importance. In this study, we aim to clarify whether the perception of declined 'CSF severity' could hypothetically reflect the adaptation of an initially high-virulent virus or whether this might be better explained as a misinterpretation of observations. A mechanistic eco-epidemiological model was employed to follow up a highly virulent strain of CSFV introduced into large connected wild boar populations. In the model, the virulence of the CSF virus is represented by case mortality and life expectancy after lethal infection. Allowing for small stochastic variation, these two characteristics of the virus are passed on with every new simulated infection that occurs. Model analysis revealed a decrease from high to moderate case mortality within a few years of simulated perpetuation of the virus. The resulting mortality corresponded to the level where the population average of the infectious period and the basic reproduction number of the disease were maximal. This shift in virulence was sufficient to prolong virus circulation considerably beyond the epidemic phase of the simulated outbreaks. Alternative mechanistic explanations for the decrease in disease severity in a CSF-affected wild boar population were evaluated in the light of the simulation experiments and the available epidemiological or virological evidence. In conclusion, the current virus isolates of subgroup 2.3 might be the ideally adapted variants of the CSF virus for long-term perpetuation in wildlife and indeed may have evolved (once) during past outbreaks in large populations. A repeated perception of a declining severity of disease pattern during the course of a CSF outbreak, however, favours the explanation based on monitoring and detection biases rather than repeated observation of selection against highly virulent virus during the time of virus perpetuation.