Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

The non-clinical and clinical Implications of Drug-induced Liver Injury – Test Systems, Clinical Research and Regulatory Aspects ***

Dr. Martin Hornberger (Abschlußjahr: 2013)

Summary
Language: English

In clinical practice Drug-induced liver injury (DILI) is a relatively low-frequent event affecting only 1 in 10 000 to 1 in 100 000 patients taking a certain drug. But because of its potential severity that can be life-threatening to the concerned subject it still is a major concern for authorities in the approval pathway of a drug, for patients, and for the pharmaceutical industry. This is highlighted by the fact that adverse events leading to DILI are the primary cause for withdrawals of drugs from the market and one very frequent cause to stop development of a drug candidate in development. More than 700 drugs have been described to cause  hepatotoxicity. DILI is responsible for 5% of all hospitalizations and 50% of all acute liver failure (ALF) cases. Due to its unique metabolic capacity and its close relationship to the gastrointestinal tract the liver is volatile to DILI. The reasons plus the fact that idiosyncratic adverse events, due to the difference of individuals is always possible, are responsible for the fact that DILI will remain an important issue for the pharmaceutical industry, regulators and patients also in the future.
The aim of this thesis is to summarize what is known today about DILI, and to describe the regulatory framework that is in place specifically addressing this topic and also defining how DILI is detected, assessed and mitigated today. The second part of this work focuses on new scientific developments that are under way to better predict DILI throughout the drug development pathway to improve patient safety.
The causality assessment of DILI relies to a large part on the biochemical injury pattern i.e. serum parameter elevations, namely alanine transaminase (ALT) and total bilirubin (TBL). The two parameters are tied together in Hy’s law to predict possibly severe cases of DILI. The height of elevations of these parameters are also used to define the three broad categories of DILI, hepatocellular, cholestatic and mixed DILI. The diagnosis is still a diagnosis of excluding other possible cause and therefore still relies in large part also on the knowledge and experience of the investigator. The view how regulatory authorities address and define DILI throughout the  drug development path and how DILI cases shall be reported is described by summarising the FDA guideline on DILI from 2009, the EMA reflection paper from 2010, and the Health Canada guideline from 2012.
The drawback of assessment parameters in place today to state the diagnosis DILI is that this is only a description that injury has already happened. What is needed to improve patient safety are ways to predict DILI earlier, more specific concerning the type of injury caused, and possibly predict also the level of severity. Therefore a lot of research today by international consortia, like the critical path initiative, the PredTox project, and the LiverTox database integrating industry, academia and competent authorities is dedicated to the identification of new biomarkers and test systems that might fulfil these needs. The task is hindered by just partly predictive animal models and the low frequency of DILI cases overall. Despite this possible biomarker candidates are still emerging. Among others miR-122, ApoE and Cytokeratin18 have the potential to at least fulfil some of the wanted aspects. But progress also comes in form of available quick breath tests and maybe the genetic identification of susceptibility alleles.
The challenge for the future lies on how to best use new scientific developments (the field of “omics”) for the decision how to abort a drug candidate as early as possible in the drug development pathway after initial signs of hepatotoxicity have been discovered, but without losing molecules that will be causing only mild, acceptable DILI in some patients but might be the only possible cure for a certain disease that other patients suffer from.

Pages:57,
Annexes:2, Pages:19