scholarly journals The development and application of in silico models for drug induced liver injury

RSC Advances ◽  
2018 ◽  
Vol 8 (15) ◽  
pp. 8101-8111 ◽  
Author(s):  
Xiao Li ◽  
Yaojie Chen ◽  
Xinrui Song ◽  
Yuan Zhang ◽  
Huanhuan Li ◽  
...  
Keyword(s):  
Pharmaceutical Industry ◽  
Liver Injury ◽  
In Silico ◽  
Nutritional Supplements ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
In Silico Models

Drug-induced liver injury (DILI), caused by drugs, herbal agents or nutritional supplements, is a major issue for patients and the pharmaceutical industry.

In silico assessment of drug-induced liver injury in humans

2016 ◽  
Vol 258 ◽  
pp. S118
Author(s):  
C. Yang ◽  
S. Thakkar ◽  
A. Mostrag ◽  
V. Gombar ◽  
B. Bienfait ◽  
...  
Keyword(s):  
Liver Injury ◽  
In Silico ◽  
Drug Induced ◽  
Drug Induced Liver Injury

Zucker Lean Rats With Hepatic Steatosis Recapitulate Asymptomatic Metabolic Syndrome and Exhibit Greater Sensitivity to Drug-Induced Liver Injury Compared With Standard Nonclinical Sprague-Dawley Rat Model

2020 ◽  
Vol 48 (8) ◽  
pp. 994-1007
Author(s):  
Timothy P. LaBranche ◽  
Anna K. Kopec ◽  
Srinivasa R. Mantena ◽  
Brett D. Hollingshead ◽  
Andrew W. Harrington ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Pharmaceutical Industry ◽  
Liver Injury ◽  
Hepatic Steatosis ◽  
Sprague Dawley ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Sd Rats ◽  
Normal Chow

Fatty liver disease is a potential risk factor for drug-induced liver injury (DILI). Despite advances in nonclinical in vitro and in vivo models to assess liver injury during drug development, the pharmaceutical industry is still plagued by idiosyncratic DILI. Here, we tested the hypothesis that certain features of asymptomatic metabolic syndrome (namely hepatic steatosis) increase the risk for DILI in certain phenotypes of the human population. Comparison of the Zucker Lean (ZL) and Zucker Fatty rats fed a high fat diet (HFD) revealed that HFD-fed ZL rats developed mild hepatic steatosis with compensatory hyperinsulinemia without increases in liver enzymes. We then challenged steatotic HFD-fed ZL rats and Sprague-Dawley (SD) rats fed normal chow, a nonclinical model widely used in the pharmaceutical industry, with acetaminophen overdose to induce liver injury. Observations in HFD-fed ZL rats included increased liver injury enzymes and greater incidence and severity of hepatic necrosis compared with similarly treated SD rats. The HFD-fed ZL rats also had disproportionately higher hepatic drug accumulation, which was linked with abnormal hepatocellular efflux transporter distribution. Here, we identify ZL rats with HFD-induced hepatic steatosis as a more sensitive nonclinical in vivo test system for modeling DILI compared with SD rats fed normal chow.

In silico weight of evidence assessment of drug-induced liver injury in humans

2017 ◽  
Vol 280 ◽  
pp. S284-S285 ◽  
Author(s):  
Chihae Yang ◽  
James Rathman ◽  
Aleksandra Mostrag ◽  
Shraddha Thakkar ◽  
Weida Tong ◽  
...  
Keyword(s):  
Liver Injury ◽  
In Silico ◽  
Weight Of Evidence ◽  
Drug Induced ◽  
Drug Induced Liver Injury

In Silico Identification of Proteins Associated with Drug-induced Liver Injury Based on the Prediction of Drug-target Interactions

2017 ◽  
Vol 36 (7) ◽  
pp. 1600142 ◽  
Author(s):  
Sergey Ivanov ◽  
Maxim Semin ◽  
Alexey Lagunin ◽  
Dmitry Filimonov ◽  
Vladimir Poroikov
Keyword(s):  
Liver Injury ◽  
In Silico ◽  
Drug Target ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
In Silico Identification

scholarly journals In silico modeling to optimize interpretation of liver safety biomarkers in clinical trials

2017 ◽  
Vol 243 (3) ◽  
pp. 300-307 ◽  
Author(s):  
Rachel J Church ◽  
Paul B Watkins
Keyword(s):  
Clinical Trials ◽  
Liver Injury ◽  
Alanine Aminotransferase ◽  
In Silico ◽  
Drug Induced ◽  
Serum Alanine Aminotransferase ◽  
Drug Induced Liver Injury ◽  
Drug Candidates ◽  
Liver Safety ◽  
In Silico Modeling

Current strategies to delineate the risk of serious drug-induced liver injury associated with drugs rely on assessment of serum biomarkers that have been utilized for many decades. In particular, serum alanine aminotransferase and total bilirubin levels are typically used to assess hepatic integrity and function, respectively. Parallel measurement of these biomarkers is utilized to identify patients with drug-induced hepatocellular jaundice (“Hy’s Law” cases) which carries at least a 10% risk of death or liver transplant. However, current guidelines regarding use of these biomarkers in clinical trials can put study subjects at risk for life-threatening drug-induced liver injury, or result in over estimation of risk that may halt development of safe drugs. In addition, pharmaceutical companies are increasingly being required to conduct large and expensive clinical trials to “defend” the safety of their new drug when results from smaller trials are inconclusive. Innovative approaches and some novel biomarkers are now being employed to maximize the value of traditional biochemical tests. DILIsym®, a product of the DILIsim Initiative, utilizes serial serum alanine aminotransferase values, along with serum biomarkers of apoptosis vs necrosis, to estimate percent hepatocyte loss and total bilirubin elevations resulting from loss of global liver function. The results from analyses conducted with DILIsym have been reported to the FDA to support the safety of entolimod and cimaglermin alfa after elevations in serum alanine aminotransferase and/or bilirubin halted clinical development. DILIsym can also be utilized to determine whether rises in serum conjugated and unconjugated bilirubin are consistent with mechanisms unrelated to toxicity ( i.e. inhibition of bilirubin transport or metabolism). In silico modeling of traditional and novel drug-induced liver injury biomarker data obtained in clinical trials may be the most efficient and accurate way to define the liver safety profile of new drug candidates. Impact statement Blood tests used in clinical trials to detect and monitor drug-induced liver injury (DILI) have not changed in half a century. These tests have several shortcomings: their use has not completely prevented clinical trial participants from risk of life-threatening DILI, they can give false positive results that halt the development of safe drug candidates, and they can create liver safety “concerns” that require large additional clinical trials to accurately define DILI risk. This review highlights the use of in silico modeling to improve interpretation of the blood tests currently available to detect DILI risk in new drug candidates. This approach is increasingly being applied in clinical trials to more precisely assess the degree of hepatocellular injury and its functional impact. This new approach holds the promise of more accurately defining DILI risk in smaller clinical trials.

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