Drug-induced liver injury: a safety review

ABSTRACT

Introduction: Idiosyncratic drug-induced liver injury (DILI) remains one of the most important causes of drug attrition both in the early phases of clinical drug development and in the postmarketing scenario. This is because, in spite of emerging data on genetic susceptibility variants associated to the risk of hepatotoxicity, the precise identification of the individual who will develop DILI when exposed to a given drug remains elusive.

Areas covered: In this review, we have addressed recent progress made and initiatives taken in the field of DILI from a safety perspective through a comprehensive search of the literature.

Expert opinion: Despite the substantial progress made over this century, new approaches using big data analysis to characterize the true incidence of DILI are needed and to categorize the drugs’ hepatotoxic potential. Genetic studies have highlighted the role of the adaptive immune system yet the mechanisms leading adaptation versus progression remain to be elucidated. There is a compelling need for development and qualification of sensitive, specific, and affordable biomarkers in DILI to foster drug development, patient treatment stratification and, improvement of causality assessment methods. Gaining mechanistic insights in DILI is essential to uncover therapeutic targets and design prospective clinical trials with appropriate endpoints.

KEYWORDS:

• Idiosyncratic drug-induced liver injury
• DILI
• hepatotoxicity
• biomarkers
• immunophenotype
• CIOM/RUCAM scale

Article highlights

• The real incidence of DILI is underestimated.

• Educational measures for clinicians and patients are needed.

• More precise diagnostic tests that is, more sensitive, specific, and affordable biomarkers of DILI are needed in order to facilitate premarketing and postmarketing detection and causality assessment.

• Hy´s law used during drug development is the best predictor of serious liver injury and a the modified (nR) Hy’s law is an improved and validated tool for predicting mortality postmarketing.

• Research on treatment options in DILI is mandatory.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

The present study has been supported by grants of the Instituto de Salud Carlos III co-founded by Fondo Europeo de Desarrollo Regional – FEDER (contract numbers: PI15/01440, PI PI16_01748), the Andalusian Health Service (SAS) (contract number: PI-0285–2016) and by the Agencia Española del Medicamento. CIBERehd is funded by Instituto de Salud Carlos III.