Abstract
Pharmacometric methods have been highlighted in clinical toxicology studies in recent years. These methods provide a quantitative understanding of the relationship between physiology and related pathologies and pharmacology. Drug overdose is an important public health problem in the area of clinical toxicology and paracetamol overdose, either intentional or unintentional, is the leading cause of acute liver failure in many countries. However, there is a lack of a comprehensive understanding of the mechanisms of hepatotoxicity and optimal treatment strategies under various paracetamol overdose scenarios as a whole. The overall aim of this thesis was to apply pharmacometric methods in clinical toxicology to understand the injury caused by drug overdose and its treatment, using paracetamol overdose as a motivating example.
A general semi-mechanistic model for cell death and biomarker release from injured tissues was developed (Chapter 2). Three components were included: (1) natural tissue turnover, (2) biomarker release after cell death and its movement from tissue to blood, (3) different insult mechanisms. The general model has sufficient flexibility to quantify various kinetic behaviours of biomarker release after tissue damage in a variety of clinical toxicology and pharmacology studies. The developed model is the first general mathematical representation of biomarker release after cellular insult and provides a new framework to facilitate a better understanding of the underlying mechanisms of toxicity events and injury processes in drug overdose.
The importance of sulfation in understanding the risk of liver toxicity secondary to paracetamol overdose was emphasised (Chapter 3). A thought model simulation illustrated that insufficient sulfation led to a shift in metabolism of paracetamol to toxic oxidation pathway and patients with low sulfate reserves may be at higher risk of paracetamol toxicity. Serum sulfate, a measurable substrate on the causal path of paracetamol hepatotoxicity, was proposed as a novel predictor for paracetamol toxicity and its treatment.
A population pharmacokinetic model for plasma concentrations of immediate-release (IR) and modified-release (MR) paracetamol and its major metabolites was developed (Chapter 4). MR paracetamol showed a slow absorption after a supratherapeutic dose intake. Model simulations showed that errors may exist in toxicity assessment based on the 150mg/L nomograms for overdose with MR paracetamol. These findings support the key update in the latest guidelines for Australia and New Zealand, where the nomogram line was no longer recommended for interpreting MR paracetamol overdose.
A 54-state quantitative systems pharmacology (QSP) model for paracetamol overdose and its rescue was developed by integrating key model components investigated in this thesis (Chapter 2 to Chapter 4) as well as prior knowledge from the literature. This unique QSP model provided a quantitative understanding of the whole causal pathway of paracetamol-induced hepatotoxicity and its treatment with the antidote N-acetylcysteine (NAC) in both IR and MR paracetamol. Various mechanisms that may affect paracetamol hepatotoxicity were explored and two subpopulations with different susceptibilities to N-acetyl-para-benzoquinone imine (NAPQI) toxicity were identified for the first time. This work identified a knowledge gap in paracetamol hepatotoxicity and further studies are needed to address this issue.
A utility analysis was performed to explore the optimal NAC regimens in various paracetamol overdose scenarios based on the QSP model simulations. Key attributes including the efficacy of protecting liver injury and the side effects caused by high exposure were considered in the utility function. It was found that slow input or impaired elimination of paracetamol could be the driving factors for NAC prolonged infusion, suggesting that larger dose or longer duration of NAC infusion is required in treating MR paracetamol overdose or massive overdose.
In conclusion, pharmacometric methods applied in this thesis provided quantitative and mechanistic insights to drug overdose induced toxicity, using paracetamol overdose as an example. A new general framework to understand and quantify biomarker release behaviours after tissue injury was developed and can be adopted in various clinical toxicology studies. The QSP model for paracetamol overdose and rescue improved the understanding of mechanisms in paracetamol-induced hepatotoxicity and its treatment with the antidote NAC. An important future work is to optimise NAC regimens in various paracetamol overdose scenarios.