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Population Pharmacokinetic Modeling of Acetaminophen Protein Adducts in Adults and Children.

  • Jiang, Sibo1
  • Madrasi, Kumpal1
  • Samant, Tanay1
  • Lagishetty, Chakradhar1
  • Vozmediano, Valvanera1
  • Chiew, Angela2, 3
  • Abdel-Rahman, Susan M4
  • James, Laura P5
  • Schmidt, Stephan1
  • 1 Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, University of Florida, Orlando, Florida, USA.
  • 2 Department of Clinical Toxicology Prince of Wales Hospital, Randwick, NSW, Australia. , (Australia)
  • 3 NSW Poisons Information Centre, Children's Hospital at Westmead, Westmead, NSW, Australia. , (Australia)
  • 4 Division of Clinical Pharmacology and Medical Toxicology, Children's Mercy Hospitals and Clinics, Kansas City, Missouri, USA.
  • 5 Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital Research Institute, Little Rock, Arkansas, USA.
Published Article
Journal of clinical pharmacology
Publication Date
Dec 04, 2019
DOI: 10.1002/jcph.1555
PMID: 31802503


Acetaminophen protein adducts (adducts) are a well-established biomarker to diagnose acetaminophen toxicity. To date, the quantitative relationship between acetaminophen exposure, which drives adduct formation, and adduct exposure remains to be established. Our study characterized the adduct formation and disposition in adults using the approach of population parent-metabolite modeling. It demonstrated formation-limited pharmacokinetics (PK) for adducts in healthy subjects. This finding expands the existing knowledge on adduct PK that showed an apparent long elimination half-life. We then allometrically scaled the adduct PK model to children, simulated the adduct profiles, and compared these simulated profiles with those observed in an independent cohort of children. The scaled model significantly overpredicted the adduct concentrations in children early on in treatment and underpredicted concentrations following repeated acetaminophen doses. These results suggest that children demonstrate different adduct PK behavior from that of adults, most likely because of increased reactive metabolite detoxification in children. In summary, we described the first PK model linking acetaminophen and acetaminophen protein adduct concentrations, which provides a semimechanistic understanding of varying profiles of adduct exposure in adults and children. © 2019, The American College of Clinical Pharmacology.

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