Liver safety biomarkers

Cytotoxicity Evaluated for confounding interpretation of in vitro efficacy assays, for predicting potential for human toxicity especially in liver but also if warranted by other safety assessments in bone marrow, kidney, neurons, immu-nocytes and so on. Also used for developing understanding of biochemical mechanisms of toxicity. HCA has been repeatedly demonstrated to be an effective tool in predictive toxicology. May also be used for certain translational safety biomarkers of toxicity [37]... 

Amacher DE (2010) The discovery and development of proteomic safety biomarkers for the detection of drug-induced liver toxicity. Toxicol Appl Pharmacol 245 (1) 134-142. doi 10.1016/j.taap.2010.02.011... 

Thulin P, Nordahl G, Gry M, Yimer G, Aklillu E, Makonnen E, Aderaye G, Lindquist L, Mattsson CM, Ekblom B, Antoine DJ, Park BK, Linder S, Harrill AH, Watkins PB, Glinghammar B, Schuppe-Koistinen I (2013) Keratin-18 and microRNA-122 complement alanine aminotransferase as novel safety biomarkers for drug-induced liver injury in two human cohorts. Liver Int. doi 10.1111/liv.l2322... 

The qualification of novel DILI biomarkers will require application to biospecimens obtained from many different patient populations treated with many different drugs, both those that cause clinically important DILI and those that cause elevations in traditional liver chemistries but do not cause clinically important liver injury. It is important that pharmaceutical companies start now to archive samples and link these specimens to the relevant liver safety data. Ideally, liver safety data management tools should be standardized across the industry to facilitate the precompetitive collaborations on biomarker validation and qualification, such as eDISH (Watkins et al., 2011). Formal biomarker validation and qualification will warrant significant time to obtain regulatory-endorsed exploratory status via Letters of Support. 

Singhal, R., et al.. Mechanistic biomarkers of liver safety and benign elevations in serum aminotransferases—a study in healthy volunteer treated with cholestyramine. BMC Pharmacology and Toxicology, 2014.15 42. 

Thulin, P, et al., Keratin-18 and microRNA-122 complement alanine aminotransferase as novel safety biomarkers for drug-induced liver injury in two human cohorts. Liver Int, 2014. 34 p. 367-78. 

A variety of biomarkers have been shown to be valuable individually for one or several toxicant or disease situations. Few of these biomarkers have been systematically evaluated for the plethora of situations that might provoke false positive responses. Acceleration of the current pace of biomarker evaluation and qualification demands (a) the availability of panels of biomarker-assays that can be comparatively evaluated on well-defined common sample sets, (b) fit-for-purpose performance evaluation in controlled animal studies with carefully benchmarked histological endpoints and samples from well-defined focused clinical trial cohorts, and (c) ready availability of banked blood and urine sample archives from clinical trial populations with carefully documented morbidities such as the Framingham Heart Study,45 or the Drug-Induced Liver Injury Network (DILIN) prospective study,46 to name a few. Availability of such panels of validated biomarker assays and well-documented preclinical and clinical samples, as well as increased cooperation between animal model researchers and clinical researchers will enable individual biomarkers to be qualified for sensitivity of specifically defined adverse events, qualified for appropriate specificity using samples of defined benign events, and collected into panels that yield complementary information about the health and safety of animals and patients. 

Miyamoto, M., Yanai, M., Ookubo, S., Awasaki, N., Takami, K., and Imai, R. 2008. Detection of cell-free, liver-specific mRNAs in peripheral blood from rats with hepatotoxicity A potential toxicological biomarker for safety evaluation. Toxicol. Sci. 106(2) 538-45. 

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