The Liver Takes It All

Drug-induced liver injuries result in more regulatory actions and delays in pharmaceutical developments than any other serious medical event. Scientists and pharma companies have created a virtual liver to better understand the effects of pharmaceutical drugs.

RESEARCH TRIANGLE PARK — There’s a new study from the non-profit medical center Mayo Clinic showing that 70% of Americans take at least one prescription drug. The survey also shows that more than half of all Americans take at least two prescription medicines.

And while all that medicine no doubt treats a variety of issues, it also poses a danger to the liver, the organ that processes everything we consume. That’s because the liver acts on the drug, while at the same time the drug also acts on the liver.

“First of all the liver metabolizes the medicines, or breaks the drug down into its by-products, so that those by-products can be excreted from our bodies safely,” says Dr. Brett Howell, Lead Scientist at the Hamner Institutes for Health Sciences. “But in addition, the liver also interacts with the drug and, in doing so, the drug can affect the other things the liver does for our body as well. So, for example, our bile acid or other things we have in our liver that process the food we eat.”

Bottom line, the organ that weighs roughly three pounds, inside an adult human, is really important. The liver produces cholesterol, regulates blood sugar and detoxifies the blood. And because the liver is so important, the risk of damage to the liver is one of biggest challenges in the development and approval of new medications. There’s a medical term for the damage the medicines can do to the organ. It’s DILI, which stands for drug-induced liver injury.

So Dr. Howell is leading a pioneering effort to better understand, and even predict, potential liver injury from medicines. He manages the DILI-sim Initiative at the Hamner Institutes. DILI-sim is a software program that includes the mathematics behind what’s going on in the liver when a person takes a drug. In particular, the program predicts the adverse effects, or damage, that a drug can have on the liver.

“DILI-sim is a combination of what the drug is doing to the liver and what the liver does to the drug over time,” adds Howell. “The key to understanding liver damage is what happens when those two things come together. Once we understand that and then put the math behind it into a software platform, then hopefully we can predict what is going to happen to human beings and to the liver when they take medications.”

Researchers enter the name of the drug and its various properties into the DILI-sim software and then run simulations of the drug’s effects. The results are displayed in a graph, showing how the medicine is metabolized over time as well as the medicine’s effects on various biomarkers, or chemicals, that are produced in the liver.

“So this is a bio-marker that is typically measured in clinical trials or if a patient is being monitored for liver injury,” explains Dr. Howell, as he points out various features and information displayed in a graph on the computer screen. “The advantage of this program is that traditionally this biomarker would be followed over time in the clinic, so the physician can get an indication of when the patient may be in danger. With DILI-sim, we are simulating what these particular patients would experience if they were taking the drug for a particular protocol.”

The software can be used at any stage along the pipeline of drug development, including the cellular level. That allows a company to get an early indication of the safety of its drug. The software can also be used in late-stage drug testing, to better understand a concern about liver safety that may have been spotted during clinical trials. There are 14 pharmaceutical companies that are partnering with the Hamner Institutes on the project. The goal of the initiative is to improve patient safety and reduce the cost and time needed to develop new drugs.

“The DILI-sim initiative is important because with certain drugs out there, it is safe for the vast majority of people and they have no problem taking the medicine,” explains Dr. Paul Watkins, Director of The Hamner-UNC Institute for Drug Safety Sciences and Chair of the DILI-sim Initiative. “However there are the rare patients who have a serious adverse event. So the FDA will say because we don’t know, and you don’t know, we either have to take it off the market or make sure it goes to people who have no other options. DILI-sim may help us better understand and predict what might happen with patients.”

The Hamner Institutes and its partners also hope DILI-sim can help in holding down the astronomical costs of drug development. It is estimated that from the time a drug is developed by the chemist to when it goes on the store shelf, almost $2 billion has been spent and 10 years have passed. That’s the typical cost and time required to go through the gauntlet of procedures and clinical trials.

“If this initiative can make a difference in bringing medicines to patients sooner, cheaper and with less risk, then we have been successful,” adds Dr. Watkins.

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