Systems Toxicology Approach to Identifying Paracetamol Overdose

Abstract

Paracetamol (acetaminophen (APAP)) is one of the most commonly used analgesics in the United Kingdom and the United States. However, exceeding the maximum recommended dose can cause serious liver injury and even death. Promising APAP toxicity biomarkers are thought to add value to those used currently and clarification of the functional relationships between these biomarkers and liver injury would aid clinical implementation of an improved APAP toxicity identification framework. The framework currently used to define an APAP overdose is highly dependent upon time since ingestion and initial dose; information that is often highly unpredictable. A pharmacokinetic/pharmacodynamic (PK/PD) APAP model has been built in order to understand the relationships between a panel of biomarkers and APAP dose. Visualization and statistical tools have been used to predict initial APAP dose and time since administration. Additionally, logistic regression analysis has been applied to histology data to provide a prediction of the probability of liver injury.

A systems toxicology paracetamol overdose framework: accounting for high-risk individuals

“…Remien et al [26] also used conventional biomarkers to predict initial dose and time since overdose. Our work in [20] extended this previous work with the inclusion of novel biomarkers HMGB1 and K18. However, there is currently only one in-silico APAP model which takes into consideration individuals that may have depleted GSH stores.…”

“…For the biomarker PD element of the model, in the original framework one experimental dataset is used [30] which records biomarkers (GSH, ALT, HMGB1, full and fragmented K18) over time following a 530 mg/kg APAP dose. In the extended framework, this dataset is also used, but with the addition of two other datasets from two separate studies [20,27]. The first, [20], provides dose response data for mouse biomarker concentrations GSH, ALT, HMGB1 and fragmented K18 at 5 hours following APAP doses [0,150,300,530,750,1000] mg/kg.…”

“…We have recently developed a framework that uses a single sample, rather than multiple sample, approach to biomarker quantification in order to predict the probability of liver injury [20]. This model was optimised against fed mouse data and therefore is limited to applications relating to individuals with unimpaired clearance capacity.…”

“…In this study, we extend our original APAP overdose framework [20] to quantify the effects of various factors that impact upon GSH availability to develop an improved overdose identification framework. The mathematical model is refined using techniques from uncertainty analysis to account for mechanistic changes indicative of suppressed GSH capacity and optimised against additional data to improve its scope and predictive potential.…”

In silico models in drug development: where we are

“…For instance, a PBPK model was coupled with the miRNA-BDNF pathway to study perfluorooctanesulfonic acid induced neurotoxicity [29]. In another study, Mason et al combined PK and mechanistic models to estimate the dose and time of ingestion in paracetamol poisoning, using traditional and experimental serum biomarkers in mice [30]**.…”