Background & Purpose

• The analgesic/antipyretic acetaminophen (APAP) has multiple formulations including immediate-, modified-, and extended-release preparations
• In 2017, the European Medicines Agency recommended suspending medicines containing a modified-release (MR) preparation from the market as there was concern that in large overdose, it could form a bezoar resulting in unexpected pharmacokinetics (PK), with markedly prolonged absorption and delayed plasma peak concentrations, compared to an immediate-release (IR) formulation
• There was also a concern that current treatment guidelines developed for APAP overdose were inappropriate for MR formulations
• In the US, the extended-release (ER) formulation of APAP (TYLENOL® 8 HR Arthritis Pain, Johnson & Johnson Consumer Inc., NJ) is designed with an IR layer and an erodible ER layer
• This project utilized a modeling and simulation approach to compare predicted PK and hepatotoxicity biomarkers following various acute overdose and repeated supratherapeutic ingestion (RSTI) scenarios to determine if there is a difference between the US APAP-IR and APAP-ER preparations

Methods

• The existing APAP-IR representation within DILIsym® v8A, a QST model of drug-induced liver injury (DILI), was updated [e.g., formation of the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI) and other APAP metabolites] using newly acquired in vitro and clinical datasets (Fig. 1)
• Exposure-dependent cytochrome P450 (CYP) 2E1- and CYP3A4-mediated contributions to NAPQI formation (>85% and <15%, respectively) were implemented
• An APAP-ER model was developed by modifying the representation of APAP absorption in the APAP-IR model to recapitulate the fast- and slow-release from IR and ER layers of the APAP-ER caplet and was verified with clinical data (Fig. 2)
• In vitro dissolution of APAP from the IR and ER formulations was experimentally evaluated using different systems (e.g., Tiny-TNO Gastro-Intestinal Model smartificialgut, Tiny-TIMsg)
• These experimental data were used as input for the Z-factor (Takano) dissolution model within GastroPlus® to inform the in vivo dose-vs-fraction absorbed (Fa) relationship for APAP-IR and APAP-ER that was subsequently leveraged within the DILIsym model (Fig. 3)
• Simulated populations (SimPops®) representing healthy adults, moderate chronic alcohol users (MCAU), excessive chronic alcohol users (ECAU), and individuals with low glutathione (GSH) were developed and verified using clinical PK and hepatic biomarker data (Fig. 4)
• The DILIsym model was then used to simulate PK and three clinically useful hepatic biomarkers [plasma alanine aminotransferase (ALT), total bilirubin (TB), and international normalized ratio (INR)] after single acute overdoses (3.9, 9.75, 19.5, 32.5, 65, 78 and 100.1 g; Fig. 5; Table 1) and RSTI (3.9, 5.2 and 7.8 g/day; Table 2) of APAP-ER and APAP-IR
• Simulations were carried out in the absence of clinical interventions (e.g., decontamination, N-acetylcysteine treatment), such that they represent worst-case scenarios

Conclusion

• Modeling and simulation consistently demonstrate that the difference in PK between the two APAP formulations in the US:
  • has a relatively small, if any, effect on APAP metabolism and biomarkers of hepatotoxicity following overdose
  • does not result in marked differences in the expected time course of APAP plasma concentrations
• Based on these results, the updated APAP overdose treatment guidelines, published in 2023, are not further impacted by this report

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

2024 SOT Annual Meeting and ToxExpo, March 10–14, 2024, Salt Lake City, Utah