Genetic test informs about potential drug-induced liver damage

Liver injury and DILI:

Drug-induced liver toxicity, also technically known as hepatotoxicity , isdefined as liver damage caused by exposure to drugs and other non-infectious substances. In the Anglo-Saxon world, the liver-damaging effect of such drugs is often referred to as drug-induced liver injury, or DILI for short.

A distinction is made between two types: intrinsic and idiosyncratic hepatotoxicity. The intrinsic form of liver injury is dose dependent and in some cases predictable. An example of this would be liver injury from the antipyretic agent acetaminophen. The idiosyncratic form, however, can occur sporadically and is therefore unpredictable - but this type of hepatotoxicity occurs with a frequency of 1 : 10,000 to 1 : 100,000. Because hepatotoxic events are often not recognized, they can easily be missed in clinical trials. Consequently, drugs could be withdrawn from the market due to such side effects.

An example of this would be Ulipristal - a progesterone receptor modulator. This has caused severe damage to the liver in patients when taken for prolonged periods of time and is therefore no longer allowed to be used since March 2020.

Study Method:

The study, published in the journal Nature Medicine in September 2020, reports on the identification of a so-called polygenic risk score (i.e. risk value). This is designed to show when a drug (approved or even under investigation) poses a risk for drug-induced liver toxicity (i.e. DILI). The work was conducted by a consortium (i.e., Temporary Enterprise Consortium) of scientists from Cincinnati Children's, Tokyo Medical and Dental University, Takeda Pharmaceutical Co. in Japan, and otherresearch centers in Japan, Europe, and the United States.

A possible reason for the severe prognosis could be the complex metabolic pathways of the liver - these are strongly influenced by genetic aspects. The polygenic risk score that has been developed should now make it easier to predict DILI.

It was generated by analyzing hundreds of genome-wide association studies (GWAS for short), which revealed about 20,000 gene variants that may influence the risk of DILI. This risk score was tested on multiple drugs and was able to identify whether there was an increased risk of liver injury. These included: Cyclosporine, Bosentan, Troglitazone, Diclofenac, Flutamide, Ketoconazole, Carbamazepine, Amoxicillin-Clavulanate, Methapyrilene, Tacrine, Paracetamol or Tolcapone.

How can a risk score help?

This would allow doctors and other medical professionals to perform a quicker genetic test to identify patients who are at higher risk for liver damage - before medications are prescribed. Consequently, the genetic test results could prompt a doctor to change dosages, order more follow-up testing to more quickly detect signs of liver disease, or change medication altogether.

In terms of research, such genetic testing could lead to the exclusion of individuals at high risk for liver toxicity from clinical trials in order to better study the benefits of a drug being tested.

Liver disease has caused a number of drug failures in the past. This was the case in a phase 3 clinical trial in 2014 - a potential diabetes treatment called fasiglifam was discontinuedbecause some study participants (ratio of about 1 : 10 000) showed elevated enzyme levels, which may indicate possible liver damage. Although such a risk rate appears minimal, at that time there was no way to determine which individuals would develop DILI, which is why this drug was deemed too dangerous. The new polygenic risk score would make it possible to createso-called liver organoids. Organoids are small pieces of tissue made in the lab that can resemble many organs. These could have important risk variants to help determine if a drug is harmful before it would ever be tested in humans.

Conclusion:

The results of the research could be a promising step toward solving the problem facing clinical drug trials. Doctors could use the genetic test to adjust dosages and medications for patients before liver damage arrives. Even drugs that have already been studied, such as fasiglifam orulipristal, could bere-approved if the polygenic risk score could be used to identify which patients should not take such drugs because they would damage their liver. In any case, further studies involving a larger population are needed to confirm initial results. Thus, such a DILI test could possibly find widespread use.

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