Experts from the University of Nottingham have helped to develop a new genetic test that can predict the risk of different medications causing liver injury.
In a new study, published today in Nature Medicine, experts have identified a "polygenic risk score" that shows when a drug, be it an approved medication or an experimental one, poses a risk of drug-induced liver injury (DILI).
For clinicians, a risk score would allow them to run a quick genetic test to identify patients at higher risk of liver injury before prescribing medications. The results might prompt a doctor to change the dosage, order more frequent follow-up tests to catch early signs of liver damage, or switch medications entirely.
For drug research, the test could help exclude people of high risk of liver injury from a clinical trial so that the benefits of a medication can be more accurately assessed.
The study was carried out by a consortium of experts from around the globe, and led by Cincinnati Children's Hospital in Ohio in the USA, in collaboration with experts from Yokohama City University, the T-CiRA Joint Program, Takeda Pharmaceutical Company, and the Tokyo Medical and Dental University in Japan; the universities of Nottingham and Newcastle in the UK; the Icahn School of Medicine at Mount Sinai in New York, and the University of North Carolina, The findings take a large step toward solving a problem that has frustrated drug developers for years.
"So far we have had no reliable way of determining in advance whether a medication that usually works well in most people might cause liver injury among a few," says Jorge Bezerra, , Director, Division of Gastroenterology, Hepatology and Nutrition at Cincinnati Children's Hospital. "That has caused a number of promising medications to fail during clinical trials, and in rare cases, also can cause serious injury from approved medications. If we could predict which individuals would be most at-risk, we could prescribe more medications with more confidence. Now that reliable test might be just around the corner."
This is the most significant breakthrough that would transform liver safety in drug development. Interestingly, discovery from patient-based research was applied to the cell-cultures in the laboratory to find an innovative solution to an obdurate problem which animal models couldn't resolve."
The team developed the risk score by re-analysing hundreds of genome-wide association studies (GWAS) that had identified a long list of gene variants that might indicate a likelihood of a poor reaction in the liver to various compounds. By combining the data and applying several mathematical weighting methods, the team found a formula that appears to work.
- The risk score takes more than 20,000 gene variants into account.
- The team confirmed the score's prediction power in cell culture, in organoid tissue and by using patient genomic data already on file.
- The score was valid in tests involving more than a dozen medications: cyclosporine, bosentan, troglitazone, diclofenac, flutamide, ketoconazole, carbamazepine, amoxicillin–clavulanate, methapyrilene. tacrine, acetaminophen and tolcapone.
- The test works for different types of drugs because the score focuses on a set of common mechanisms involved in how the liver metabolizes a drug, including oxidant stress pathways in liver cells and endoplasmic reticulum (ER) stress—a disruption of cell function that happens when proteins cannot fold properly.
Liver toxicity has caused a number of drug failures over the years. Takanori Takebe, corresponding author, an organoid expert at Cincinnati Children's says both patients and the drug maker were disappointed when a potential diabetes treatment called fasigliam was withdrawn in 2014 during phase 3 clinical trials. Some of the participants (at a rate equivalent to about 1 in 10,000) experienced elevated enzyme levels that suggested potential liver injury.
While such risks may appear low, at the time there was no way to predict which people would develop DILI, making the drug unacceptably dangerous. But the new polygenic risk score would make it possible to produce liver organoids that exhibit key risk variants to determine if a drug is harmful before people ever take it.
The full study can be found here.
