title: Population pharmacokinetic study of gentamicin in a large cohort of premature and term neonates.
abstract: OBJECTIVE
  This study aims to investigate the clinical and demographic factors influencing gentamicin pharmacokinetics in a large cohort of unselected premature and term newborns and to evaluate optimal regimens in this population.
  
  
  METHODS
  All gentamicin concentration data, along with clinical and demographic characteristics, were retrieved from medical charts in a Neonatal Intensive Care Unit over 5 years within the frame of a routine therapeutic drug monitoring programme. Data were described using non-linear mixed-effects regression analysis ( nonmem®).
  
  
  RESULTS
  A total of 3039 gentamicin concentrations collected in 994 preterm and 455 term newborns were included in the analysis. A two compartment model best characterized gentamicin disposition. The average parameter estimates, for a median body weight of 2170 g, were clearance (CL) 0.089 l h(-1) (CV 28%), central volume of distribution (Vc ) 0.908 l (CV 18%), intercompartmental clearance (Q) 0.157 l h(-1) and peripheral volume of distribution (Vp ) 0.560 l. Body weight, gestational age and post-natal age positively influenced CL. Dopamine co-administration had a significant negative effect on CL, whereas the influence of indomethacin and furosemide was not significant. Both body weight and gestational age significantly influenced Vc . Model-based simulations confirmed that, compared with term neonates, preterm infants need higher doses, superior to 4 mg kg(-1) , at extended intervals to achieve adequate concentrations.
  
  
  CONCLUSIONS
  This observational study conducted in a large cohort of newborns confirms the importance of body weight and gestational age for dosage adjustment. The model will serve to set up dosing recommendations and elaborate a Bayesian tool for dosage individualization based on concentration monitoring.
authors.affiliation: Division of Clinical Pharmacology, Service of Biomedicine, Department of Laboratory, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
authors.forename: Aline
authors.initials: A
authors.lastname: Fuchs
authors.forename: Monia
authors.initials: M
authors.lastname: Guidi
authors.forename: Eric
authors.initials: E
authors.lastname: Giannoni
authors.forename: Dominique
authors.initials: D
authors.lastname: Werner
authors.forename: Thierry
authors.initials: T
authors.lastname: Buclin
authors.forename: Nicolas
authors.initials: N
authors.lastname: Widmer
authors.forename: Chantal
authors.initials: C
authors.lastname: Csajka
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood*; D001724:Birth Weight; D001835:Body Weight; D015331:Cohort Studies; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D016231:Fluorescence Polarization Immunoassay; D005839:Gentamicins / Q000008:administration & dosage / Q000097:blood*; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn / Q000097:blood*; D007234:Infant, Premature / Q000097:blood*; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D057285:Precision Medicine; D012044:Regression Analysis; D012189:Retrospective Studies
chemical_list: D000900:Anti-Bacterial Agents; D005839:Gentamicins
keywords: aminoglycoside; dosing guidelines; neonates; population pharmacokinetics; therapeutic drug monitoring; two compartment model