Modeling of drug-induced liver injury has explained why troglitazone caused delayed, life-threatening liver injury in some patients but was not hepatotoxic in rats, according to a new study published in Clinical Pharmacology & Therapeutics.1
Troglitazone, one of the first thiazolidinedione drugs approved for type 2 diabetes, was withdrawn from the market after cases of liver failure were reported. This type of low-incidence, severe hepatotoxicity is often not detected in phase 3 trials involving a few thousand patients.
This study reports on a systems pharmacology model that can more accurately predict the inhibition of bile acid transport. This model was able to correctly predict species differences in the hepatotoxicity of troglitazone and the relative liver safety of pioglitazone.
Pioglitazone is from the same therapeutic class but has generated less concern about hepatotoxicity.
“We are trying to help develop safer drugs. The goal is to identify, at an early stage, which drugs cause damage to the liver, and which patients might be more susceptible to adverse liver reactions,” said study researcher Kim Brouwer, PharmD, PhD, William R. Kenan, Jr. Distinguished Professor and Chair of the Division of Pharmacotherapy and Experimental Therapeutics at the University of North Carolina Eshelman School of Pharmacy.
The researchers used the model to investigate altered bile acid homeostasis as a mechanism of the hepatotoxicity of troglitazone. Their systems pharmacology model incorporated drug/metabolite disposition, bile acid physiology/pathophysiology, hepatocyte life cycle and liver injury biomarkers.
The model found that troglitazone resulted in hepatotoxicity in the simulated human population while pioglitazone did not, which is consistent with clinical data. In the simulated rat population, troglitazone was not hepatotoxic.
“Integrating physiological and biochemical information using computer-based models can result in more accurate predictions about which drugs might cause liver injury. This approach may help identify patient-specific factors that predispose certain individuals to adverse liver events,” Dr. Brouwer told Endocrinology Advisor.
This model may aid in more accurately predicting the risk for liver injury in humans that is drug-induced and bile acid-mediated, the researchers wrote. Drug-induced liver injury is a primary reason why pharmaceuticals fail during development as well as why approved drugs are withdrawn from the market.
“Help is on the way to assure physicians that new and important drugs will be safe for the liver in all their patients,” said Paul Watkins, MD, Director of the Hamner–UNC Institute for Drug Safety Sciences, Professor at the UNC Eshelman School of Pharmacy, and Verne S. Caviness Distinguished Professor at the UNC School of Medicine.
“This study showed that a newly developed computer model of the liver was able to predict liver failure in rare patients on troglitazone. The results suggest that this approach could be helpful in improving the safety of new drugs in the future,” Dr. Watkins said in an interview.