title: Neonatal Maturation of Paracetamol (Acetaminophen) Glucuronidation, Sulfation, and Oxidation Based on a Parent-Metabolite Population Pharmacokinetic Model.
abstract: This study aimed to model the population pharmacokinetics of intravenous paracetamol and its major metabolites in neonates and to identify influential patient characteristics, especially those affecting the formation clearance (CLformation) of oxidative pathway metabolites.
  
  
  
  Neonates with a clinical indication for intravenous analgesia received five 15-mg/kg doses of paracetamol at 12-h intervals (<28 weeks' gestation) or seven 15-mg/kg doses at 8-h intervals (≥28 weeks' gestation). Plasma and urine were sampled throughout the 72-h study period. Concentration-time data for paracetamol, paracetamol-glucuronide, paracetamol-sulfate, and the combined oxidative pathway metabolites (paracetamol-cysteine and paracetamol-N-acetylcysteine) were simultaneously modeled in NONMEM 7.2.
  
  
  
  The model incorporated 259 plasma and 350 urine samples from 35 neonates with a mean gestational age of 33.6 weeks (standard deviation 6.6). CLformationfor all metabolites increased with weight; CLformationfor glucuronidation and oxidation also increased with postnatal age. At the mean weight (2.3 kg) and postnatal age (7.5 days), CLformationestimates (bootstrap 95% confidence interval; between-subject variability) were 0.049 L/h (0.038-0.062; 62 %) for glucuronidation, 0.21 L/h (0.17-0.24; 33 %) for sulfation, and 0.058 L/h (0.044-0.078; 72 %) for oxidation. Expression of individual oxidation CLformationas a fraction of total individual paracetamol clearance showed that, on average, fractional oxidation CLformationincreased <15 % when plotted against weight or postnatal age.
  
  
  
  The parent-metabolite model successfully characterized the pharmacokinetics of intravenous paracetamol and its metabolites in neonates. Maturational changes in the fraction of paracetamol undergoing oxidation were small relative to between-subject variability.
authors.affiliation: Department of Pharmacology and Toxicology, Center for Human Toxicology, University of Utah, Salt Lake City, UT, USA.
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Cook
authors.affiliation: Division of Clinical Pharmacology, Department of Pediatrics, University of Utah School of Medicine, 295 Chipeta Way, Salt Lake City, UT, 84108, USA.|Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Stockmann
authors.affiliation: Division of Clinical Pharmacology, Children's National Health System, Washington, DC, USA.|Division of Neonatology, Department of Pediatrics, McMaster University, Hamilton, ON, Canada.
authors.forename: Samira
authors.initials: S
authors.lastname: Samiee-Zafarghandy
authors.affiliation: Department of Pharmacology and Toxicology, Center for Human Toxicology, University of Utah, Salt Lake City, UT, USA.
authors.forename: Amber D
authors.initials: AD
authors.lastname: King
authors.affiliation: Division of Anesthesiology, Sedation, and Perioperative Medicine, Children's National Health System, Washington, DC, USA.
authors.forename: Nina
authors.initials: N
authors.lastname: Deutsch
authors.affiliation: Division of Clinical Pharmacology, Children's National Health System, Washington, DC, USA.
authors.forename: Elaine F
authors.initials: EF
authors.lastname: Williams
authors.affiliation: Department of Pharmacology and Toxicology, Center for Human Toxicology, University of Utah, Salt Lake City, UT, USA.|Division of Medical Laboratory Sciences, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA.
authors.forename: Diana G
authors.initials: DG
authors.lastname: Wilkins
authors.affiliation: Division of Clinical Pharmacology, Department of Pediatrics, University of Utah School of Medicine, 295 Chipeta Way, Salt Lake City, UT, 84108, USA. catherine.sherwin@hsc.utah.edu.|Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA. catherine.sherwin@hsc.utah.edu.|Clinical Trials Office, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA. catherine.sherwin@hsc.utah.edu.
authors.forename: Catherine M T
authors.initials: CM
authors.lastname: Sherwin
authors.affiliation: Division of Clinical Pharmacology, Children's National Health System, Washington, DC, USA.|Departments of Pediatrics, Integrative Systems Biology, Pharmacology and Physiology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.|Intensive Care and Department of Pediatric Surgery, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.|Department of Paediatric Pharmacology, University Children's Hospital Basel, Basel, Switzerland.
authors.forename: John N
authors.initials: JN
authors.lastname: van den Anker
mesh_terms: D000082:Acetaminophen / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*; D018712:Analgesics, Non-Narcotic / Q000493:pharmacokinetics*; D003545:Cysteine / Q000031:analogs & derivatives* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D008297:Male; D008954:Models, Biological; D010290:Parents; D011446:Prospective Studies
chemical_list: D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; C069744:acetaminophen cysteine; C037386:acetaminophen glucuronide; D003545:Cysteine; C045667:acetaminophen sulfate ester