Why a deadly drug didn’t hurt lab rat livers

"It turns out that animals do a poor job predicting human drug-induced liver injury," says Kim Brouwer. "There are lots of explanations, but one important reason is that bile acids are different in each species." (Credit: iStockphoto)

Scientists believe they’ve solved the mystery of why a diabetes drug introduced in 1997 caused fatal liver failure in 63 patients.

Their discovery makes it likely that similar drug-related deaths can be prevented in the future.

In 1997, troglitazone was approved for use in the United States as one of the first drugs designed to treat type 2 diabetes. It was withdrawn from the market in 2000 after 63 people died from liver failure after taking it.

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No one at the time really understood what happened. In preclinical studies using rats, there was no sign of danger to the liver. During human trials, adverse effects from the drug were characterized as rare and relatively mild. There were some hints at the potential for liver damage, but they weren’t enough to prevent approval by the Food and Drug Administration.

“Rats didn’t have a problem handling the drug, and the human trials weren’t large enough for the true risk of liver injury to become apparent,” says Paul Watkins, coauthor of the study and professor of medicine and pharmacy at University of North Carolina. He is the director of the Hamner-UNC Institute for Drug Safety Sciences.

“Once the drug was given to a larger population that contained patients unable to properly process the drug, people started to turn yellow and die of liver failure.”

Were bile acids to blame?

The research team at the UNC Eshelman School of Pharmacy used DILIsym, a computer program designed to predict how drugs will affect the liver. The team combined information about troglitazone with data specific to the human liver generated in the lab of senior author Kim Brouwer, a professor at the pharmacy school.

In a simulated population, the model successfully predicted that rare patients would develop life-threatening liver injury while also suggesting what factors make these patients susceptible. The team’s findings are published online in Clinical Pharmacology and Therapeutics.

“The simulation we used was able to predict the effects that were seen in patients who actually took troglitazone when it was on the market,” says Kyunghee Yang, lead author of the study. “In addition to this, the model was also able to describe the mechanisms that may have caused the liver damage.”

The researchers cite the accumulation of bile acids, substances produced by the liver that promote digestion and aid in the absorption of fats, as the most likely suspect in the deaths.

“Bile acids are like detergents,” Yang says. “If they accumulate in the liver, they can cause cell death. Increased bile acid concentrations in the liver may lead to liver damage. This is one of the possible mechanisms we proposed.”

Beyond animal testing

The study shows that a computer model could accurately forecast the occurrence of troglitazone-induced liver injury. The model also predicted that rats respond differently to the drug than humans, a critical insight as animal testing precedes human trials.

“Before DILIsym, no one had been able to completely explain troglitazone liver injury or suggest improved approaches so drug companies could avoid similar problems in the future,” Brouwer says.

“It turns out that animals do a poor job predicting human drug-induced liver injury. There are lots of explanations, but one important reason is that bile acids are different in each species. Recent data suggest that the use of humanized systems has greater predictive power for adverse events like DILI.”

Drug-induced liver injury is the most common reason drug-development programs are terminated. It is also the leading cause of regulatory actions that lead to failed or stalled drug approvals, market withdrawals, usage restrictions, and warnings to physicians, Watkins says.

“Rare liver toxicity is now the major safety concern with new drugs and can often be detected only after many thousands of patients have received treatment,” Watkins says. “We believe that the application of DILIsym will greatly improve drug safety while minimizing animal testing and reducing the costs of new medicines.”

The DILIsym software is the result of the DILI-sim Initiative, a partnership between the Hamner-UNC Institute for Drug Safety Sciences and fourteen major drug companies that shared data to develop a tool that can predict a drug’s risk of injuring the liver.

Kyunghee Yang is currently a postdoctoral fellow at the Hamner Institutes. Paul Watkins is chairman of the DILI-sim Scientific Advisory Board. Kim Brouwer is chair of the Division of Pharmacotherapy and Experimental Therapeutics at the UNC Eshelman School of Pharmacy.

Funding for the study came from the National Institute of General Medical Sciences.

Source: UNC-Chapel Hill