Consensus Guidelines: Best Practices for Detection, Assessment and Management of Suspected Acute Drug-Induced Liver Injury During Clinical Trials in Adults with Chronic Viral Hepatitis and Adults with Cirrhosis Secondary to Hepatitis B, C and Nonalcoholic Steatohepatitis

Abstract

With the widespread development of new drugs to treat chronic liver diseases (CLDs), including viral hepatitis and nonalcoholic steatohepatitis (NASH), more patients are entering trials with abnormal baseline liver tests and with advanced liver injury, including cirrhosis. The current regulatory guidelines addressing the monitoring, diagnosis, and management of suspected drug-induced liver injury (DILI) during clinical trials primarily address individuals entering with normal baseline liver tests. Using the same laboratory criteria cited as signals of potential DILI in studies involving patients with no underlying liver disease and normal baseline liver tests may result in premature and unnecessary cessation of a study drug in a clinical trial population whose abnormal and fluctuating liver tests are actually due to their underlying CLD. This position paper focuses on defining best practices for the detection, monitoring, diagnosis, and management of suspected acute DILI during clinical trials in patients with CLD, including hepatitis C virus (HCV) and hepatitis B virus (HBV), both with and without cirrhosis and NASH with cirrhosis. This is one of several position papers developed by the IQ DILI Initiative, comprising members from 16 pharmaceutical companies in collaboration with DILI experts from academia and regulatory agencies. It is based on an extensive literature review and discussions between industry members and experts from outside industry to achieve consensus regarding the recommendations. Key conclusions and recommendations include (1) the importance of establishing laboratory criteria that signal potential DILI events and that fit the disease indication being studied in the clinical trial based on knowledge of the natural history of test fluctuations in that disease; (2) establishing a pretreatment value that is based on more than one screening determination, and revising that baseline during the trial if a new nadir is achieved during treatment; (3) basing rules for increased monitoring and for stopping drug for potential DILI on multiples of baseline liver test values and/or a threshold value rather than multiples of the upper limit of normal (ULN) for that test; (4) making use of more sensitive tests of liver function, including direct bilirubin (DB) or combined parameters such as aspartate transaminase:alanine transaminase (AST:ALT) ratio or model for end-stage liver disease (MELD) to signal potential DILI, especially in studies of patients with cirrhosis; and (5) being aware of potential confounders related to complications of the disease being studied that may masquerade as DILI events. The views expressed are those of the authors and do not necessarily represent the position of, nor imply endorsement from, the US Food and Drug Administration or the US Government.

Prognostic Value of Aspartate Transaminase/Alanine Transaminase Ratio in Patients With Hepatitis B Virus-Related Hepatocellular Carcinoma Undergoing Hepatectomy

“…The serum levels of AST and ALT, two key enzymes in the biological process, are routinely assessed for liver function prior to clinical treatment ( 20 ). The De Ritis ratio (AST/ALT) was initially thought to be a valuable diagnostic marker for the etiology of hepatitis (e.g., acute viral hepatitis) ( 8 ), while the association between an elevated De Ritis ratio and poor prognosis of various cancers has been subsequently found ( 21 – 24 ), including HCC ( 25 – 27 ).…”

AGL9: A Novel Hepatoprotective Peptide from the Larvae of Edible Insects Alleviates Obesity-Induced Hepatic Inflammation by Regulating AMPK/Nrf2 Signaling

“…Lipid accumulation in liver parenchymal cells and subsequent toxicity can result from excessive inflammation and liver damage [ 21 ]. Moreover, HFD can cause an increase in free fatty acids (FFAs) in serum, with the continuous accumulation of FFAs causing liver damage, increasing cell-membrane permeability and the release of ALT and AST into the circulation, where they are frequently used as important markers of the degree of liver damage [ 22 ]. In the present study, we observed increases in serum ALT and AST levels accompanied by increases in TC, TG, and LDL levels and a decrease in HDL content in NAFLD mice.…”

Opportunities and challenges in translational science

“…Such a systematic understanding would allow candidate interventional molecules of all types to be made with low adverse event liability from the beginning, the current practice of making many molecules with unpredictable liabilities, most of which fail in later stages of testing. Several industry‐based and public‐private partnerships have made early progress in predictive toxicology via massive data generation and sharing efforts, including the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) biopharmaceutical collaborative drug safety program (e.g., Treem et al 29 ); the BioCelerate subsidiary of the pharmaceutical company collaborative TransCelerate BioPharma Inc.; the Critical Path Institute's Predictive Safety Testing Consortium (e.g., Schomaker et al 30 ), and the Innovative Medicines Initiative eTox 31 and TransQST programs. The Toxicology in the 21st Century program, a collaborative effort among NCATS, the National Toxicology Program, the Environmental Protection Agency, and the US Food and Drug Administration (FDA) has also made promising advances in this area, 32 but much more needs to be achieved before accurate and reliable prediction of common and idiosyncratic toxicities is possible.…”