A novel approach for estimating ingested dose associated with paracetamol overdose

Abstract

AIMIn cases of paracetamol (acetaminophen, APAP) overdose, an accurate estimate of tissue-specific paracetamol pharmacokinetics (PK) and ingested dose can offer health care providers important information for the individualized treatment and follow-up of affected patients. Here a novel methodology is presented to make such estimates using a standard serum paracetamol measurement and a computational framework. METHODSThe core component of the computational framework was a physiologically-based pharmacokinetic (PBPK) model developed and evaluated using an extensive set of human PK data. Bayesian inference was used for parameter and dose estimation, allowing the incorporation of inter-study variability, and facilitating the calculation of uncertainty in model outputs. RESULTSSimulations of paracetamol time course concentrations in the blood were in close agreement with experimental data under a wide range of dosing conditions. Also, predictions of administered dose showed good agreement with a large collection of clinical and emergency setting PK data over a broad dose range. In addition to dose estimation, the platform was applied for the determination of optimal blood sampling times for dose reconstruction and quantitation of the potential role of paracetamol conjugate measurement on dose estimation. CONCLUSIONSCurrent therapies for paracetamol overdose rely on a generic methodology involving the use of a clinical nomogram. By using the computational framework developed in this study, serum sample data, and the individual patient's anthropometric and physiological information, personalized serum and liver pharmacokinetic profiles and dose estimate could be generated to help inform an individualized overdose treatment and follow-up plan. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Many of the pharmacokinetic measures used to characterize paracetamol overdoses were derived from therapeutic dosing studies.• Current assessment and treatment plans for paracetamol overdose cases generally rely on a generic methodology involving the use of a clinical nomogram.• Self-reported dose alone is a poor predictor of risk following paracetamol overdose, and lack of accurate knowledge of the ingested dose may hamper the effective long term management of these cases. WHAT THIS STUDY ADDS• It provides a well-validated paracetamol PBPK model for humans under overdose conditions and a clinically-useful methodology for paracetamol dose estimation.• It elucidates the effect of blood sampling time and additional biomarker measurements on dose reconstruction.• It demonstrates a means to generate personalized serum and liver pharmacokinetic profiles and a dose estimate that should prove useful in developing an individualized overdose treatment and follow-up plan.

Physiologically Based Pharmacokinetic Modeling to Characterize Acetaminophen Pharmacokinetics and N-Acetyl-p-Benzoquinone Imine (NAPQI) Formation in Non-Pregnant and Pregnant Women

“…If these are insufficient, biologically plausible assumptions must be made. Previously, well-validated PBPK models have been developed of acetaminophen in other special populations [25][26][27]. Although these models could be used to further validate the predictions of both acetaminophen and its metabolites throughout different stages of pregnancy once adequate clinical data are available, those models were not used here as, for example, it was unknown whether pregnancy itself changes the levels of the co-factors for acetaminophen glucuronidation and sulfation.…”

Physiologically Based Pharmacokinetic Model of Rifapentine and 25-Desacetyl Rifapentine Disposition in Humans

“…To include the effects of data uncertainty and interstudy variability on model outputs, unknown parameters were estimated within a Bayesian hierarchical context (26)(27)(28). Within this context, parameters were estimated by first computing partition coefficients and other relevant parameters for the R-PBPK and then using these parameter distributions as "priors" in the estimation of the human-specific parameters.…”

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

“…Zurlinden et al [24] used a Bayesian inference approach within a PBPK model to estimate initial APAP dose and quantify its uncertainty based on conventional biomarkers. Our model aims to optimise patient stratification and overdose treatment by incorporating a panel of novel mechanism-based biomarkers of increased sensitivity [25].…”