Drug-Induced Liver Injury Throughout the Drug Development Life Cycle: Where We Have Been, Where We are Now, and Where We are Headed. Perspectives of a Clinical Hepatologist

The Art and Science of Diagnosing and Managing Drug-induced Liver Injury in 2015 and Beyond

“…The prognosis for these patients with iDILI is often very poor with a high case-fatality rate without urgent liver transplantation (15,16). As a result, the concern for acute iDILI progressing to ALF has kept drug-induced hepatotoxicity a perennial target of regulatory actions , and the ongoing focus of both pre-approval and as well as postmarketing drug development safety efforts ( 6,(17)(18)(19)(20)(21)(22).…”

“…The potential for a new chemical entity (NCE) to cause serious liver injury has been among the leading reasons why novel compounds are either halted in the early phases of testing , are not approved for use, or have been withdrawn in the post-marketing setting (17,21,23). Given the significant time and expense involved in bringing an innovative drug to market, it should not be surprising that substantial effort is aimed at identifying potentially program-ending toxicities as early as possible in the drug development process (17).…”

“…Given the significant time and expense involved in bringing an innovative drug to market, it should not be surprising that substantial effort is aimed at identifying potentially program-ending toxicities as early as possible in the drug development process (17). In silico modeling (24), structural alerts (25) and other preclinical methodologies are routinely employed to avoid bringing forward molecules that are potentially hepatotoxic (26-31).…”

“…However, as not all compounds can be guaranteed to be free of liver injury in the pre-clinical stages, the past decade has also seen enormous strides made in the field of regulatory science to identify DILI in the clinical (49, 52). Although such efforts have brought us closer to understanding why DILI occurs, gaps in our knowledge base still remain (2,4,17). While pharmacogenomics is being actively pursued in an effort to uncover genetic risk factors predicting susceptibility to DILI (54, 55, 97, 98), how best to incorporate such new information into clinical practice, and how to define its clinical utility, remain to be determined (99-104).…”

“…Through their collective efforts over the past 15 years, members of the FDA, academia, and industry have collaborated to collect and share resources on a global scale to better understand and predict hepatotoxicity (4,5,17,20,(105)(106)(107)(108)(109)(110).…”