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P106: Drug-induced Liver Injury – Significance in Premarketing Clinical Trials

Poster Presenter

Sumit Verma

President, Clinical Safety and Pharmacovigilance
Soterius
United States

Objectives

DILI, a rare but potentially fatal adverse drug reaction is a common cause of failure to obtain marketing authorizations or resulting in marketing authorization withdrawals. The objective is to explore methods to detect and evaluate hepatotoxicity and develop a mechanism to detect potential DILI.

Method

DILI can be detected by monitoring liver enzyme elevations, hepatic adverse events, identifying cases with Hy’s law, use of graphic tools for assessing liver enzyme elevations e.g., eDISH Plots, Kaplan-Meier plots, and assessing mechanisms of DILI.

Results

DILI Risk Assessment Based on Liver Enzyme Elevations: Hy's Law is essentially a translation of Zimmerman's finding that hyperbilirubinemia caused by pure hepatocellular injury is an ominous sign of a drug's potential to cause substantial liver injury. Hy’s Law cases have following 3 elements: •The drug causes hepatocellular injury, generally shown by >3xUpper Limit of Normal (ULN) of aminotransferases (ATs) ALT or AST than the (nonhepatotoxic) control drug or placebo. •Among trial subjects showing such AT elevations, often with ATs much greater than 3xULN, one or more also show elevation of serum Total bilirubin (TBL) to >2xULN, without initial findings of cholestasis (elevated serum ALP). •No other reason can be found to explain combination of increased AT and TBL, such as viral hepatitis A, B, or C; preexisting or acute liver disease; or another drug capable of causing the observed injury. Finding 1 Hy’s Law case in a clinical trial is worrying; finding 2 cases is considered highly suggestive that when given to a larger population, the drug has the potential to cause severe DILI. Graphical Assessment of Liver Enzyme Elevations: 1. eDISH Plots - A graphical presentation to analyze liver safety profile of a drug for all study subjects and to find any idiosyncratic cases. The data in eDISH plots is displayed in 4 quadrants. The below figure is based on dummy data and is for illustrational purpose only. 2.Kaplan-Meier plot – A graphical presentation that displays and compares time to event onset. To interpret and manage the study drug effects on the liver, it is important to compare and understand the time to elevation of liver test results among treatment groups. Drugs can cause liver injuries through varied mechanisms. These injuries can look like almost any type of liver disease, and there are no pathognomonic findings, even on liver biopsy, that confirm a diagnosis of DILI. The mechanisms and risk factors for DILI are poorly understood in most cases.

Conclusion

DILI is a key concern for regulators, drug developers, and physicians. DILI is difficult to predict during drug development process. As severe DILI is generally rare, finding a single case may require treatment of thousands of people from varied patient populations. The clinical trials present an exclusive opportunity to detect hepatotoxicity and cases of potential DILI with a study drug prior to its use in general population. The two main categories of DILI signals include a) an inequality among study subjects having elevated liver enzymes with higher number of these subjects in study drug group as compared to the placebo (comparator) group and b) cases of clinically significant DILI with elevated bilirubin, jaundice, hepatic symptoms or coagulopathy. Monitoring the liver test abnormalities is useful for assessing trends over time and to analyze imbalance between study drug and placebo/comparator groups. Further, due to the limited number of subjects in a clinical trial, monitoring the standard serum liver tests to detect milder liver injury can be considered a predominant approach to predict the risk of possible DILI in clinical trials. This can be further supplemented by use of graphic tools for assessing liver enzyme elevations e.g., eDISH Plots and Kaplan-Meier plots. Considering that there may be varied mechanisms of DILI and different clinicopathological phenotypes, a systematic collection of adequate diagnostic datasets along with a focused causality assessment performed by clinical professionals having expertise in this area is required for the evaluation of each potential case of DILI in clinical trials.