PT  - JOURNAL ARTICLE
AU  - Jeffrey L. Woodhead
AU  - Brett A. Howell
AU  - Yuching Yang
AU  - Alison H. Harrill
AU  - Harvey J. Clewell III
AU  - Melvin E. Andersen
AU  - Scott Q. Siler
AU  - Paul B. Watkins
TI  - An Analysis of <em>N</em>-Acetylcysteine Treatment for Acetaminophen Overdose Using a Systems Model of Drug-Induced Liver Injury
AID  - 10.1124/jpet.112.192930
DP  - 2012 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 529--540
VI  - 342
IP  - 2
4099  - http://jpet.aspetjournals.org/content/342/2/529.short
4100  - http://jpet.aspetjournals.org/content/342/2/529.full
SO  - J Pharmacol Exp Ther2012 Aug 01; 342
AB  - 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. Vmax 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.