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

Experimental Biology and Medicine
Rachel J Church, Paul B Watkins

Abstract

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...Continue Reading

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Citations

Nov 1, 2018·Journal of Digestive Diseases·Rachel J Church, Paul B Watkins
Oct 12, 2018·Clinical Pharmacology and Therapeutics·Jae-Yong ChungPaul B Watkins
Feb 15, 2019·Clinical and Translational Science·Paul B Watkins
Mar 14, 2019·Current Opinion in Gastroenterology·Hans L TillmannDon C Rockey
Jun 6, 2018·Briefings in Bioinformatics·Francesco PappalardoMarco Viceconti
Jun 25, 2020·Toxicological Sciences : an Official Journal of the Society of Toxicology·Brenda SmithPeter J Goadsby
Aug 17, 2018·Expert Review of Gastroenterology & Hepatology·Michele S BarnhillJames H Lewis
Nov 19, 2020·Evidence-based Complementary and Alternative Medicine : ECAM·Cheng ZhangYuting Xie
Aug 23, 2020·Transplantation·Katie L ConnorEwen M Harrison

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Methods Mentioned

BETA
biopsy
eDISH
biopsies

Software Mentioned

ALT
eDISH
DILIsym
DILIsym®

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