title: A novel approach for estimating ingested dose associated with paracetamol overdose.
abstract: OBJECTIVE
  In 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.
  
  
  METHODS
  The 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.
  
  
  RESULTS
  Simulations 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.
  
  
  CONCLUSIONS
  Current 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.
authors.affiliation: Department of Chemical and Biological Engineering, Colorado State University, Fort Collins, Colorado, 80523-1370.
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Zurlinden
authors.affiliation: Department of Emergency Medicine, University of Colorado School of Medicine, 12401 E. 17th Avenue Campus Box B-215, Aurora, CO, 80045.|Rocky Mountain Poison and Drug Center, Denver, CO, 80204.
authors.forename: Kennon
authors.initials: K
authors.lastname: Heard
authors.affiliation: Department of Chemical and Biological Engineering, Colorado State University, Fort Collins, Colorado, 80523-1370.|School of Biomedical Engineering, Colorado State University, Fort Collins, Colorado, 80523-1376, USA.
authors.forename: Brad
authors.initials: B
authors.lastname: Reisfeld
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D062787:Drug Overdose / Q000097:blood*; D006801:Humans; D008954:Models, Biological; D011237:Predictive Value of Tests; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D000082:Acetaminophen
keywords: Bayesian; PBPK; acetaminophen; overdose; paracetamol; pharmacokinetic