An Analysis ofN-Acetylcysteine Treatment for Acetaminophen Overdose Using a Systems Model of Drug-Induced Liver Injury

Abstract

N-acetylcysteine (NAC) is the treatment of choice for acetaminophen poisoning; standard 72-h oral or 21-h intravenous protocols are most frequently used. There is controversy regarding which protocol is optimal and whether the full treatment course is always necessary. It would be challenging to address these questions in a clinical trial. We used DILIsym, a mechanistic simulation of drug-induced liver injury, to investigate optimal NAC treatment after a single acetaminophen overdose for an average patient and a sample population (n ϭ 957). For patients presenting within 24 h of ingestion, we found that the oral NAC protocol preserves more hepatocytes than the 21-h intravenous protocol. In various modeled scenarios, we found that the 21-h NAC infusion is often too short, whereas the full 72-h oral course is often unnecessary. We found that there is generally a good correlation between the time taken to reach peak serum alanine aminotransferase (ALT) and the time taken to clear N-acetyl-p-benzoquinone imine (NAPQI) from the liver. We also found that the most frequently used treatment nomograms underestimate the risk for patients presenting within 8 h of overdose ingestion. V max for acetaminophen bioactivation to NAPQI was the most important variable in the model in determining interpatient differences in susceptibility. In conclusion, DILIsym predicts that the oral NAC treatment protocol, or an intravenous protocol with identical dosing, is superior to the 21-h intravenous protocol and ALT is the optimal available biomarker for discontinuation of the therapy. The modeling also suggests that modification of the current treatment nomograms should be considered.

Evaluation of Three-Dimensional Cultured HepG2 Cells in a Nano Culture Plate System: an In Vitro Human Model of Acetaminophen Hepatotoxicity

“…NAC, a precursor of GSH that causes NAPQI detoxification, has been shown to produce remarkable effects against APAP-induced hepatotoxicity in rodents and humans (22,30,31). In the present study, NAC demonstrated such preventive effects against APAP-induced cell injury in NCP-cultured HepG2 cells but did not exhibit any effects on cell injury in the conventionallycultured HepG2 cells.…”

Exploring BSEP inhibition-mediated toxicity with a mechanistic model of drug-induced liver injury

“…DILIsym® describes the intrahepatic accumulation of these toxic bile acids as well as the concentrations in the gallbladder, portal blood, gut lumen, and systemic blood. Concentrations of bile acid transporter inhibitors are modeled using a physiologically-based pharmacokinetic model (PBPK) described in depth in previous papers (Howell et al, 2012; Woodhead et al, 2012). The bile acid concentrations are linked to ATP decline as described below; the effect of ATP decline on eventual hepatocyte necrosis is described by a model of the hepatocyte life cycle also described in previous papers (Howell et al, 2012; Woodhead et al, 2012; Shoda et al, 2014).…”

“…DILIsym® is a multi-scale mechanistic model incorporating numerous functions of the liver and disruptions of the function with the goal of predicting the DILI potential of drugs at various stages in the development process (Howell et al, 2012, 2014; Woodhead et al, 2012; Shoda et al, 2014). Previously, we have constructed and validated a model of bile acid homeostasis and transporter inhibition within DILIsym® (Woodhead et al, 2014).…”

Prediction of Safety Margin and Optimization of Dosing Protocol for a Novel Antibiotic using Quantitative Systems Pharmacology Modeling

“…The basic DILIsym PBPK model framework consists of a compartmental model of the body with compartments for blood, gut, liver, muscle, and other tissues and has been described in previous publications 5, 8, 15. Because BAL30072 has been shown to be a substrate of organic anion transporter (OAT)1, OAT3, organic anion‐transporting polypeptide (OATP)1B1, and OATP1B3,4 the saturable liver uptake model was used for BAL30072.…”