title: Population pharmacokinetics of cefazolin before, during and after cardiopulmonary bypass to optimize dosing regimens for children undergoing cardiac surgery.
abstract: The objective of this study was to characterize cefazolin serum pharmacokinetics in children before, during and after cardiopulmonary bypass (CPB), in order to derive an evidence-based dosing regimen.
  
  
  
  This study included children who received cefazolin before surgical incision, before cessation of CPB and after surgery. Blood samples of total and unbound cefazolin concentrations were collected before, during and after CPB. The cefazolin concentration-time profiles were analysed using population pharmacokinetic modelling and predictors for interindividual variability in pharmacokinetic parameters were investigated. Subsequently, optimized dosing regimens were developed using stochastic simulations. Clinicaltrials.gov: NCT02749981.
  
  
  
  A total of 494 total and unbound cefazolin concentrations obtained from 56 children (aged 6 days to 15 years) were included. A two-compartment model with first-order elimination plus an additional compartment for the effect of CPB best described the data. Clearance (1.56 L/h), central volume (1.93 L) and peripheral volume (2.39 L) were allometrically scaled by body weight. The estimated glomerular filtration rate (eGFR) was identified as a covariate on clearance and the serum albumin concentration was associated with maximum protein binding capacity. Our simulations showed that an additional bolus dose at the start of CPB improves the PTA in typical patients from 59% to >94%. Prolonged surgery and preserved renal function (i.e. drop in eGFR <25%) had a negative impact on PTA.
  
  
  
  We propose an optimized dosing regimen for cefazolin during cardiac surgery in paediatric patients to avoid treatment failure due to inadequate antibiotic prophylaxis.
authors.affiliation: Department of Pharmacy, Ghent University Hospital, Ghent, Belgium.|Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium.|Department of Paediatric Intensive Care, Ghent University Hospital, Ghent, Belgium.
authors.forename: Pieter A J G
authors.initials: PA
authors.lastname: De Cock
authors.affiliation: Department of Pharmacy, University Hospitals of Leicester, Glenfield Hospital, Leicester, UK.
authors.forename: Hussain
authors.initials: H
authors.lastname: Mulla
authors.affiliation: Department of Pharmacy, Ghent University Hospital, Ghent, Belgium.|Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Desmet
authors.affiliation: Department of Cardiac Surgery, Ghent University Hospital, Ghent, Belgium.
authors.forename: Filip
authors.initials: F
authors.lastname: De Somer
authors.affiliation: Department of Chemical Pathology, Pathology Queensland, Queensland, Australia.
authors.forename: Brett C
authors.initials: BC
authors.lastname: McWhinney
authors.affiliation: Department of Chemical Pathology, Pathology Queensland, Queensland, Australia.
authors.forename: Jacobus P J
authors.initials: JP
authors.lastname: Ungerer
authors.affiliation: Department of Anaesthesiology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Annelies
authors.initials: A
authors.lastname: Moerman
authors.affiliation: Department of Pharmacy, Ghent University Hospital, Ghent, Belgium.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Commeyne
authors.affiliation: Department of Paediatric Nephrology, Ghent University Hospital, Ghent, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Vande Walle
authors.affiliation: Department of Cardiac Surgery, Ghent University Hospital, Ghent, Belgium.
authors.forename: Katrien
authors.initials: K
authors.lastname: Francois
authors.affiliation: Leiden Academic Centre for Drug Research, Cluster Systems Pharmacology, Division of Pharmacology, Leiden, The Netherlands.
authors.forename: Johan G C
authors.initials: JG
authors.lastname: Van Hasselt
authors.affiliation: Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: De Paepe
mesh_terms: D000293:Adolescent; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D019072:Antibiotic Prophylaxis; D002315:Cardiopulmonary Bypass; D002437:Cefazolin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D011153:Population; D011446:Prospective Studies
chemical_list: D000900:Anti-Bacterial Agents; D002437:Cefazolin