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Watkins P.B.,Hamner UNC Institute for Drug Safety science | Desai M.,Johnson and Johnson Pharmaceutical Research and Development | Berkowitz S.D.,Bayer AG | Peters G.,Johnson and Johnson Pharmaceutical Research and Development | And 3 more authors.
Drug Safety | Year: 2011

Background: The most specific indicator of a drug-induced liver injury signal in a clinical trial database is believed to be the occurrence of subjects experiencing drug-associated elevations in both serum ALT and serum total bilirubin (TB) without a significant elevation in serum alkaline phosphatase (ALP). eDISH (evaluation of Drug-Induced Serious Hepatotoxicity) is a recently described tool that organizes liver laboratory data by graphically displaying peak serum ALT and TB levels for each subject, and can also provide direct links to the pertinent clinical and laboratory data for each subject. Objective: To illustrate the usefulness of the eDISH approach in the presentation of liver safety data by using phase III clinical trial data for rivaroxaban. Methods: Four randomized, active-controlled studies were conducted worldwide in subjects undergoing elective hip or knee replacement surgery to compare the efficacy and safety of the anticoagulant rivaroxaban, an oral, direct Factor Xa inhibitor, with the low-molecular-weight heparin, enoxaparin. Liver laboratory assessments, including ALT, AST, TB and ALP, were performed frequently during the studies. Data were incorporated into eDISH and linked data for selected subjects were analysed. Results: In the pooled analysis of the four studies, a total of 12 262 subjects (6131 rivaroxaban, 6131 enoxaparin) received at least one dose of study drug and had at least one central and/or local laboratory assessment during the study. A total of 143 (2.33%) rivaroxaban subjects and 223 (3.64%) enoxaparin subjects experienced a peak ALT >3 × upper limit of normal (ULN) but did not experience an elevation of TB >2 × ULN; these subjects are displayed in the right lower quadrant of the eDISH plot, termed the 'Temple's Corollary quadrant'. There were ten rivaroxaban and ten enoxaparin subjects with a peak ALT >3 ×ULN and a peak TB >2 × ULN; these subjects were displayed in the right upper quadrant of the eDISH plot, termed the 'Hy's Law quadrant'. eDISH allowed efficient examination of the relevant data for each of these subjects. Conclusions: The eDISH approach is an efficient and effective way to organize and examine large liver safety databases for randomized controlled clinical trials. It greatly facilitates a systematic and transparent examination of the relevant liver safety laboratory data. We believe eDISH should become a standard approach for assessing and studying liver safety issues in clinical trials. © 2011 Adis Data Information BV. All rights reserved. Source


Jeffries R.E.,University of North Carolina at Chapel Hill | Gamcsik M.P.,University of North Carolina at Chapel Hill | Keshari K.R.,University of North Carolina at Chapel Hill | Pediaditakis P.,University of North Carolina at Chapel Hill | And 5 more authors.
Tissue Engineering - Part C: Methods | Year: 2013

Many oxygen mass-transfer modeling studies have been performed for various bioartificial liver (BAL) encapsulation types; yet, to our knowledge, there is no experimental study that directly and noninvasively measures viability and metabolism as a function of time and oxygen concentration. We report the effect of oxygen concentration on viability and metabolism in a fluidized-bed NMR-compatible BAL using in vivo 31P and 13C NMR spectroscopy, respectively, by monitoring nucleotide triphosphate (NTP) and 13C-labeled nutrient metabolites, respectively. Fluidized-bed bioreactors eliminate the potential channeling that occurs with packed-bed bioreactors and serve as an ideal experimental model for homogeneous oxygen distribution. Hepatocytes were electrostatically encapsulated in alginate (avg. diameter, 500 μm; 3.5×107 cells/mL) and perfused at 3 mL/min in a 9-cm (inner diameter) cylindrical glass NMR tube. Four oxygen treatments were tested and validated by an in-line oxygen electrode: (1) 95:5 oxygen:carbon dioxide (carbogen), (2) 75:20:5 nitrogen:oxygen:carbon dioxide, (3) 60:35:5 nitrogen:oxygen:carbon dioxide, and (4) 45:50:5 nitrogen:oxygen:carbon dioxide. With 20% oxygen, β-NTP steadily decreased until it was no longer detected at 11 h. The 35%, 50%, and 95% oxygen treatments resulted in steady β-NTP levels throughout the 28-h experimental period. For the 50% and 95% oxygen treatment, a 13C NMR time course (∼5 h) revealed 2- 13C-glycine and 2-13C-glucose to be incorporated into [2-13C-glycyl]glutathione (GSH) and 2-13C-lactate, respectively, with 95% having a lower rate of lactate formation. 31P and 13C NMR spectroscopy is a noninvasive method for determining viability and metabolic rates. Modifying tissue-engineered devices to be NMR compatible is a relatively easy and inexpensive process depending on the bioreactor shape. © 2013, Mary Ann Liebert, Inc. Source


Church R.J.,Hamner UNC Institute for Drug Safety science | Gatti D.M.,The Jackson Laboratory | Urban T.J.,Duke University | Long N.,Duke University | And 12 more authors.
Food and Chemical Toxicology | Year: 2015

Consumer use of herbal and dietary supplements has recently grown in the United States and, with increased use, reports of rare adverse reactions have emerged. One such supplement is green tea extract, containing the polyphenol epigallocatechin gallate (EGCG), which has been shown to be hepatotoxic at high doses in animal models. The Drug-Induced Liver Injury Network has identified multiple patients who have experienced liver injury ascribed to green tea extract consumption and the relationship to dose has not been straightforward, indicating that differences in sensitivity may contribute to the adverse response in susceptible people. The Diversity Outbred (DO), a genetically heterogeneous mouse population, provides a potential platform for study of interindividual toxicity responses to green tea extract. Within the DO population, an equal exposure to EGCG (50 mg/kg; daily for three days) was found to be tolerated in the majority of mice; however, a small fraction of the animals (16%; 43/272) exhibited severe hepatotoxicity (10-86.8% liver necrosis) that is analogous to the clinical cases. The data indicate that the DO mice may provide a platform for informing risk of rare, adverse reactions that may occur in consumer populations upon ingestion of concentrated herbal products. © 2014 The Authors. Source


Winnike J.H.,University of North Carolina at Chapel Hill | Li Z.,University of North Carolina at Chapel Hill | Wright F.A.,University of North Carolina at Chapel Hill | MacDonald J.M.,University of North Carolina at Chapel Hill | And 4 more authors.
Clinical Pharmacology and Therapeutics | Year: 2010

Achieving the ability to identify individuals who are susceptible to drug-induced liver injury (DILI) would represent a major advance in personalized medicine. Clayton et al. demonstrated that the pattern of endogenous metabolites in urine could predict susceptibility to acetaminophen-induced liver injury in rats. We designed a clinical study to test this approach in healthy adults who received 4g of acetaminophen per day for 7 days. Urine metabolite profiles obtained before the start of treatment were not sufficient to distinguish which of the subjects would develop mild liver injury, as indicated by a rise in alanine aminotransferase (ALT) to a level more than twice the baseline value (responders). However, profiles obtained shortly after the start of treatment, but prior to ALT elevation, could distinguish responders from nonresponders. Statistical analyses revealed that predictive metabolites included those derived from the toxic metabolite N-acetyl paraquinone imine (NAPQI), but that the inclusion of endogenous metabolites was required for significant prediction. This early-intervention pharmaco-metabonomics approach should now be tested in clinical trials of other potentially hepatotoxic drugs. © 2010 American Society for Clinical Pharmacology and Therapeutics. Source


O'Connell T.M.,Hamner UNC Institute for Drug Safety science | O'Connell T.M.,University of North Carolina at Chapel Hill | Watkins P.B.,Hamner UNC Institute for Drug Safety science | Watkins P.B.,University of North Carolina at Chapel Hill
Clinical Pharmacology and Therapeutics | Year: 2010

The occurrence of drug-induced liver injury (DILI) presents a significant safety issue for patients and represents a major cause of regulatory action. The methods that are in current use for early detection and prediction of DILI in patients are not adequate. The liver is the major site of synthesis of endogenous metabolites, and data suggest that alterations in the profiles of endogenous metabolites ("the metabolome") may precede development of clinically overt DILI. Metabonomics involves the application of analytical technologies such as nuclear magnetic resonance and mass spectrometry to detect changes in the metabolome. In this review, we describe the emerging role of metabonomics in predicting and understanding the mechanisms underlying DILI. Recent human clinical trials of drugs, including acetaminophen (APAP) and ximelagatran, have shown that the metabonomics of biofluids (plasma and urine) collected before and immediately after dosing can identify individual patients who are likely to develop DILI. These studies support the need to include metabonomic investigations in clinical trials of potentially hepatotoxic medications. © 2010 American Society for Clinical Pharmacology and Therapeutics. Source

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