03 November, 2017

6 crucial facts about DILI you ought to know

By Guy Webber

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Drug induced liver injury (DILI) is a major cause of safety-related drug withdrawal and black box warnings post-market. It is also a major cause of drug attrition during development. One of the main concerns about DILI is that it is often undetected until clinical development and/or post-market approval, when the molecule is exposed to larger populations. 

So what do you need to know about DILI that will help you to reduce the risk of hepatotoxicity in humans?  Here are six facts to keep in mind.


SCIENCE Test tubes pink.jpg1. There are two types of toxicity associated with DILI

Type A toxicity, also referred to as intrinsic, is dose-dependent and reproducible and is therefore predictable (such as with acetaminophen/paracetamol).

Type B, often referred to as idiosyncratic, generally, is not predictable.  This type of toxicity is particularly problematic as it is typically not dose-dependent (although there does appear to be some relationship with total daily dose). It is also not predicted from animal safety studies.  Idiosyncratic DILI is commonly a rare event – and is characterized by low frequency (as few as 1:10,000 individuals may be affected). However, where it does occur the effects can be extremely serious and associated with high morbidity.  Its low frequency means that often it is not detected during clinical trials. Hence detection often occurs once the drug is approved and moves into a much larger patient population, sometimes becoming a major reason for post-market withdrawal.

 2. The cost of adverse drug reactions is increasing

A study recorded the following stats related to the cost of adverse drug reactions (ADRs).

Type A toxicity ADRs:

  • 100,000 fatalities per year
  • 5% of hospital admissions
  • Has cost the United States $136 billion
  • Are the fourth to sixth leading casuse of death

Type B toxicity ADRs:

  • Idiosyncratic ADRs constitute 25% of serious ADRs
  • Are a leading cause of drug withdrawal and regulatory authorities are sensitized
  • Have cost and ethical implications to the pharmaceutical industry (not detected in animal testing)

3. Potential impact scenarios of DILI are serious

The decision to progress a molecule that is displaying DILI-positive characteristics is an extremely high risk decision and should only be made after taking into account multiple factors including the therapeutic area, whether the molecule will be meeting a currently unmet need (first in class) and likely human dose (lower human doses significantly reduce the risk of DILI). Take a look at our white paper to discover specific potential impact scenarios of DILI.

4. Reactive metabolites contribute to DILI

Although precise mechanisms of DILI are still being understood (including mitochondrial dysfunction and inhibition of drug transporters for example), one pathway increasingly believed to contribute is via the formation of reactive metabolites (RM). RMs are short-lived, highly reactive, electrophilic (+ve) metabolites (sometimes radicals) which can bind to macromolecules such as hepatic proteins, antibodies and DNA causing both Type A (direct, e.g. genotoxicities) and Type B (idiosyncratic, e.g. DILI) toxicity.

The detection of RM formation is therefore a key component of de-risking strategy.  Today, RM formation can be assessed using various in vitro assays, either directly using so-called RM trapping assays or via surrogate markers such as covalent binding or time-dependent inhibition of CYP enzymes.

5. Covalent binding is a useful assay for DILI risk assessment

In covalent binding assays, the molecule is incubated with human liver microsomes and following a period of metabolic bio-activation the samples are exhaustively extracted to recover all of the drug-related material. A shortfall in mass-balance (inability to be able to extract all total drug-related material) can be indicative that the test compound is being metabolically activated to a metabolite, which is covalently bound to the microsomal protein.  Positive and negative controls should always be included to assess how the level of binding with the test compound compares to known drugs that are DILI-positive and those that are not covalently bound and are negative for DILI. For this assay, having a radiolabeled form of the drug to use is preferable.

6. DILI risk assessment cannot rely on RM trapping and covalent binding alone

Covalent binding and RM trapping comprise two very useful assays for DILI risk assessment. However, the overall assessment should not be made on one or two parameters alone. Other crucial aspects to consider when making the overall DILI risk assessment are outlined in a white paper I authored earlier this year.

For more detail about DILI, listen to the webinar presented by Guy Webber.

Drug induced liver injury (DILI) Stream the webinar today

About the author

Guy Webber, Scientific Manager, In vitro and drug-drug interaction sciences at Envigo, has 25 years’ experience in Pharma and Contract Research, working on hundreds of drug molecules for many different clients.

Category // Pharmaceutical development, drug metabolism, drug induced liver injury