Abstract

Acetaminophen (APAP) has been formulated as immediate-, modified-, and extended-release tablets (APAP-IR, -MR, and -ER,respectively). However, there was concern that APAP-MR previously available in Europe could form a bezoar after a large over-dose, leading to delayed absorption and atypical pharmacokinetics (PK) compared to APAP-IR, and that current treatmentguidelines developed for APAP overdose to prevent severe hepatotoxicity are inappropriate for APAP-MR. In contrast, APAP-ERcaplets available in the United States are designed with an IR layer and an erodible ER layer. Using modeling and simulation,predicted PK and hepatotoxicity biomarkers following various acute overdose and repeated supratherapeutic ingestion (RSTI)scenarios with APAP-IR and APAP-ER were compared to investigate the differences between these two formulations. The exist-ing APAP-IR representation within DILIsym v8A, a quantitative systems toxicology model of drug-induced liver injury, was up-dated, and an APAP-ER model was developed, using newly acquired in vitro (e.g., tiny-TIMsg) and clinical data. The model andsimulated populations (SimPops) representing healthy adults were extensively validated, before simulating PK and three clini-cally useful hepatic biomarkers after various overdose scenarios. On average, APAP exposure after acute overdose and RSTI inhealthy adults was predicted to be slightly lower for APAP-ER compared to APAP-IR, partially due to lower APAP absorption forAPAP-ER, while not markedly impacting the expected time course of APAP plasma concentrations. Similar hepatic biomarkerprofiles were predicted for both APAP formulations. Based on these results, the APAP overdose consensus treatment guidelinesupdated in 2023 are not further impacted by this report.

By James J. Beaudoin, Kyunghee Yang, Brett A. Howell, Zackary Kenz, Vinal V. Lakhani, Jeffrey L. Woodhead, John C. K. Lai, Cathy K. Gelotte, Sury Sista, Evren Atillasoy