title: Covariates of intravenous paracetamol pharmacokinetics in adults.
abstract: BACKGROUND
  Pharmacokinetic estimates for intravenous paracetamol in individual adult cohorts are different to a certain extent, and understanding the covariates of these differences may guide dose individualization. In order to assess covariate effects of intravenous paracetamol disposition in adults, pharmacokinetic data on discrete studies were pooled.
  
  
  METHODS
  This pooled analysis was based on 7 studies, resulting in 2755 time-concentration observations in 189 adults (mean age 46 SD 23 years; weight 73 SD 13 kg) given intravenous paracetamol. The effects of size, age, pregnancy and other clinical settings (intensive care, high dependency, orthopaedic or abdominal surgery) on clearance and volume of distribution were explored using non-linear mixed effects models.
  
  
  RESULTS
  Paracetamol disposition was best described using normal fat mass (NFM) with allometric scaling as a size descriptor. A three-compartment linear disposition model revealed that the population parameter estimates (between subject variability,%) were central volume (V1) 24.6 (55.5%) L/70 kg with peripheral volumes of distribution V2 23.1 (49.6%) L/70 kg and V3 30.6 (78.9%) L/70 kg. Clearance (CL) was 16.7 (24.6%) L/h/70 kg and inter-compartment clearances were Q2 67.3 (25.7%) L/h/70 kg and Q3 2.04 (71.3%) L/h/70 kg. Clearance and V2 decreased only slightly with age. Sex differences in clearance were minor and of no significance. Clearance, relative to median values, was increased during pregnancy (F(PREG) = 1.14) and decreased during abdominal surgery (F(ABDCL) = 0.715). Patients undergoing orthopaedic surgery had a reduced V2 (F(ORTHOV) = 0.649), while those in intensive care had increased V2 (F(ICV) = 1.51).
  
  
  CONCLUSIONS
  Size and age are important covariates for paracetamol pharmacokinetics explaining approximately 40% of clearance and V2 variability. Dose individualization in adult subpopulations would achieve little benefit in the scenarios explored.
authors.affiliation: Department of Development and Regeneration, KU Leuven, Leuven, Belgium ; Neonatal Intensive Care Unit, University Hospitals Leuven, Herestraat 49, Leuven, Belgium.
authors.forename: Karel
authors.initials: K
authors.lastname: Allegaert
authors.affiliation: Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Olkkola
authors.affiliation: School of Pharmacy, University of Otago, Dunedin, New Zealand.
authors.forename: Katie H
authors.initials: KH
authors.lastname: Owens
authors.affiliation: Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium ; Department of Anaesthesiology, University Hospital Leuven, Leuven, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Van de Velde
authors.affiliation: Department of Clinical Pharmacy, Rijnstate Hospital Arnhem, Arnhem, The Netherlands.
authors.forename: Monique M
authors.initials: MM
authors.lastname: de Maat
authors.affiliation: Department of Anaesthesiology, University of Auckland, Auckland, New Zealand.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Anderson
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003198:Computer Simulation; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D019637:Orthopedic Procedures; D010149:Postoperative Pain / Q000188:drug therapy; D011247:Pregnancy; D055815:Young Adult
chemical_list: D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen