Quantitative Systems Toxicology Modeling of Acetaminophen Pharmacokinetics and Hepatic Biomarkers After Overdoses of Extended-Release and Immediate-Release Formulations in Adults With Chronic Alcohol Use or Low Glutathione.

Acetaminophen (APAP), an over-the-counter analgesic and antipyretic, can cause hepatotoxicity when ingested in large overdoses. APAP has multiple formulations including immediate-release (IR) and extended-release (ER) preparations. A recently published consensus statement on the management of APAP poisoning indicated that management of APAP-ER overdose is the same as that for APAP-IR overdose. Consistent with this consensus, it was previously reported that quantitative systems toxicology (QST) modeling using DILIsym predicted similar pharmacokinetic (PK) and hepatic biomarker profiles for the APAP-ER and APAP-IR formulations after overdose in healthy adults. Hepatic injury from APAP is caused by the reactive metabolite, N-acetyl-ρ-benzoquinone imine (NAPQI), which is formed predominantly by CYP2E1-mediated metabolism and eliminated by hepatic glutathione. As such, conditions that can increase NAPQI production (e.g., CYP2E1 induction by alcohol) or decrease hepatic glutathione stores (e.g., underling liver disease) may impact PK and susceptibility to hepatotoxicity after overdose of APAP-IR and APAP-ER. In the current study, APAP-IR and APAP-ER models in chronic alcohol users and individuals with low hepatic glutathione were developed and verified within DILIsym. Simulations using verified models predicted similar PK and hepatic biomarker profiles for the APAP-ER and APAP-IR formulations in moderate and excessive chronic alcohol users and adults with low hepatic glutathione levels after single acute overdoses up to ~100 g and repeat supratherapeutic ingestions (up to 7.8 g/day for 10 days). These results further support that approaches to manage APAP-IR overdoses can be applied to manage APAP-ER overdoses in adults with chronic alcohol consumption or lower hepatic glutathione levels.