title: An analysis of N-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 = 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.
authors.affiliation: The Hamner-University of North Carolina Institute for Drug Safety Sciences, The Hamner Institutes, Research Triangle Park, North Carolina, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Woodhead
authors.forename: Brett A
authors.initials: BA
authors.lastname: Howell
authors.forename: Yuching
authors.initials: Y
authors.lastname: Yang
authors.forename: Alison H
authors.initials: AH
authors.lastname: Harrill
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Clewell
authors.forename: Melvin E
authors.initials: ME
authors.lastname: Andersen
authors.forename: Scott Q
authors.initials: SQ
authors.lastname: Siler
authors.forename: Paul B
authors.initials: PB
authors.lastname: Watkins
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000506:poisoning*; D000111:Acetylcysteine / Q000008:administration & dosage*; D000284:Administration, Oral; D000410:Alanine Transaminase / Q000378:metabolism; D016227:Benzoquinones / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000378:metabolism; D015331:Cohort Studies; D003198:Computer Simulation; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007097:Imines / Q000378:metabolism; D007262:Infusions, Intravenous; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D063487:Prescription Drug Misuse; D012307:Risk Factors
chemical_list: D016227:Benzoquinones; D007097:Imines; D000082:Acetaminophen; D000410:Alanine Transaminase; C028473:N-acetyl-4-benzoquinoneimine; D000111:Acetylcysteine