Serum biomarkers of drug‐induced liver injury: Current status and future directions

Abstract

Drug‐induced liver injury (DILI), which is caused by drugs and herbal or dietary supplements, remains a serious concern for drug developers, regulators, and clinicians; however, serum biomarkers utilized to detect and monitor DILI have not changed in decades and have limitations. Data‐driven mathematical modeling that incorporates the release and clearance kinetics of traditional biomarkers has improved their use in the prediction of liver safety liabilities for new drug candidates. Several newer biomarkers have shown promise in terms of liver specificity, predicting the outcome of DILI events, and providing insight into its underlying mechanisms. For these new biomarkers to be qualified for regulatory acceptance, it will require their assessment in large numbers of patients who are receiving a wide range of compounds and who develop a broad spectrum of liver injuries. The ongoing and evolving international biomarker consortia should play a major role in this effort, which is likely to transform the assessment of liver safety in clinical trials and in the clinic.

Diagnostic Biomarkers in Liver Injury by Drugs, Herbs, and Alcohol: Tricky Dilemma after EMA Correctly and Officially Retracted Letter of Support

“…Biomarkers of idiosyncratic DILI differ in their intentional use and may now best be classified as diagnostic or prognostic biomarkers [14,24]. Both biomarker types have been discussed in a variety of contexts [11][12][13][14][24][25][26][27][28][29][30][31][32][33], whereas the current analysis focuses on only diagnostic biomarkers. These must be used prior to prognostic biomarkers for DILI case evaluation since a prognosis depends on a correct diagnosis.…”

“…Scientific, regulatory, and consortia publications have focused on idiosyncratic or intrinsic DILI and diagnostic biomarkers that include microRNA-122 (microarray RNA-122), microRNA-192, CK-18 (Cytokeratin-18 full length), ccCK-18 (caspase-cleaved CytoKeratin-18), Cytokeratin-18 (fragments), GLDH (Glutamate dehydrogenase), total HMGB-1 (High Mobility Group Box), hyperacetylated HMGB-1, and ITGB3 (Integrin beta 3). Some of these are listed in Table 1 and have been discussed in the scientific literature [14,17,[24][25][26][27]33]. However, on 15 April 2019, confusion emerged due to the EMA issuing a retraction note regarding various potential biomarkers listed above due to external data manipulation [17].…”

“…Church [24] Considered as liver specific but this biomarker is also produced by non-hepatic cancerous cells, thereby questioning liver specificity characteristics.…”

“…Church [24] Previously proposed by SAFE-T consortium: Liver specific, early marker possibly preceding ALT on a temporal scale. Reported as sensitive DILI marker in multiple clinical studies, but robustness of specificity and sensitivity data for idiosyncratic DILI not provided.…”

“…Other parameters presented in the literature as biomarkers are disappointing from a clinical and regulatory view because most of them have nothing in common with potential diagnostic biomarkers (Table 1) [14,24,25]. The most relevant reasons are data presentation and interpretation incoherencies related to assumed diagnostic biomarkers and evident from rarely defined idiosyncratic DILI, missing DILI causality assessment (such as RUCAM), lack of diagnostic clinical criteria for liver injury, missing or ongoing validity testing, unknown targeted organ, liver injury and drug specificities, and unclear superiority over existing diagnostic biomarkers such as ALT and ALP.…”