Recent advances in biomarkers and therapeutic interventions for hepatic drug safety – false dawn or new horizon?

ABSTRACT

Introduction: Drug-induced liver injury (DILI) represents a serious medical challenge and a potentially fatal adverse event. Currently, DILI is a diagnosis of exclusion, and whilst the electronic evaluation of serious drug-induced hepatotoxicity (eDISH) have revolutionised the early assessment of DILI, this model is dependent upon clinical chemistry parameters that lack sensitivity and specificity. DILI management usually consists of initial withdrawal of the suspected drug and, in the case of acetaminophen, administration of specific therapy.

Areas covered: We summarise recent advances and knowledge gaps in the development and qualification of novel DILI biomarkers and therapeutic interventions.

Expert opinion: Promising biomarkers have been identified that provide increased hepatic specificity (miR-122), mechanistic insight (Keratin-18), and prognostic information (HMGB1, KIM-1, CSF-1). Pharmacogenomics holds potential to preselect susceptible populations and tailor drug therapy. Biomarkers can uncover new mechanisms of drug-induced pathophysiology which, for HMGB1 and CSF-1, have led to promising mechanism-based therapeutic interventions. However, these biomarkers have not been formally qualified and are not in routine clinical use. With the development of inventive clinical trials and by maximising DILI data registries, these novel biomarkers could add substantial value to the current armoury, change the management of DILI in the near future and improve patient safety.

KEYWORDS:

• Acetaminophen
• DILI
• idiosyncratic
• qualification

Article highlights.

• Drug-induced liver injury is a major clinical concern and a lack of both sensitivity and specificity of currently used clinical chemistry parameters limits its understanding and leads to under reporting.

• Promising biomarkers have been identified from studies of acetaminophen hepatotoxicity that provide added information on hepatic specificity (miR-122), mechanistic insight (Keratin-18, GLDH) and prognosis (HMGB1, KIM-1, CSF-1).

• The development of biomarkers that provide new understanding about the mechanisms of drug-induced hepatic pathophysiology hold potential to facilitate new strategies for targeted therapeutic intervention.

• Currently knowledge gaps include biomarkers specific for the diagnosis of DILI, defined healthy reference ranges, the performance of these biomarkers in idiosyncratic DILI and in prospective clinical trials of new medicines and the development of biomarkers that can distinguish benign changes in ALT activity from serious clinical DILI.

• This article challenges current concepts in the development of new DILI biomarkers and provides insights into new methodologies to test DILI biomarker performance in man.

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Financial and competing interests disclosure

J.I Clarke was supported by the Medical Research Council (MRC) PhD Studentship. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.