A systems pharmacology model for paracetamol overdose and treatment

Paracetamol overdose is the leading cause of acute liver failure in many countries, including North America and the United Kingdom. While timely administration with the standard treatment is generally effective, the optimal treatment for scenarios such as "massive" overdose or modified release paracetamol overdose remains unknown. In this work we aim to develop and calibrate a systems pharmacology model for paracetamol-induced hepatotoxicity with the influence of administration of the antidote N-acetylcysteine (NAC). The system model integrates five components, including (1) input of paracetamol, (2) paracetamol metabolism of parent drug and metabolites, (3) physiological turnover of endogenous sulfur-containing substrates, including the metabolism of cysteine to produce glutathione and inorganic sulfate, etc., (4) a general model for the release of biomarkers from injured hepatocytes to blood, and (5) a PK model for NAC and three proposed mechanisms of NAC effect. The final systems model demonstrated a good description of the concentration-time courses of paracetamol, its metabolites and biomarkers after administration of a normal dose to a large overdose of paracetamol. The final model provides a quantitative and comprehensive understanding of the causal pathway of paracetamol-induced liver toxicity and its treatment, which allows the investigation of the 'what if' scenarios in the rescue of paracetamol poisoning.