title: Novel model-based dosing guidelines for gentamicin and tobramycin in preterm and term neonates.
abstract: OBJECTIVE
  In the heterogeneous group of preterm and term neonates, gentamicin and tobramycin are mainly dosed according to empirical guidelines, after which therapeutic drug monitoring and subsequent dose adaptation are applied. In view of the variety of neonatal guidelines available, the purpose of this study was to evaluate target concentration attainment of these guidelines, and to propose a new model-based dosing guideline for these drugs in neonates.
  
  
  METHODS
  Demographic characteristics of 1854 neonates (birth weight 390-5200 g, post-natal age 0-27 days) were extracted from earlier studies and sampled to obtain a test dataset of 5000 virtual patients. Monte Carlo simulations on the basis of validated models were undertaken to evaluate the attainment of target peak (5-12 mg/L) and trough (<0.5 mg/L) concentrations, and cumulative AUC, with the existing and proposed guidelines.
  
  
  RESULTS
  Across the entire neonatal age and weight range, the Dutch National Formulary for Children, the British National Formulary for Children, Neofax and the Red Book resulted in adequate peak but elevated trough concentrations (63%-90% above target). The proposed dosing guideline (4.5 mg/kg gentamicin or 5.5 mg/kg tobramycin) with a dosing interval based on birth weight and post-natal age leads to adequate peak concentrations with only 33%-38% of the trough concentrations above target, and a constant AUC across weight and post-natal age.
  
  
  CONCLUSIONS
  The proposed neonatal dosing guideline for gentamicin and tobramycin results in improved attainment of target concentrations and should be prospectively evaluated in clinical studies to evaluate the efficacy and safety of this treatment.
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Pyry A J
authors.initials: PA
authors.lastname: Valitalo
authors.affiliation: Division of Pediatric Clinical Pharmacology, Children's National Medical Center, Washington, DC, USA Department of Pediatric Pharmacology, University Children's Hospital Basel, Switzerland Intensive Care and Department of Pediatric Surgery, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: John N
authors.initials: JN
authors.lastname: van den Anker
authors.affiliation: Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
authors.forename: Karel
authors.initials: K
authors.lastname: Allegaert
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Roosmarijn F W
authors.initials: RF
authors.lastname: de Cock
authors.affiliation: Intensive Care and Department of Pediatric Surgery, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Matthijs
authors.initials: M
authors.lastname: de Hoog
authors.affiliation: Department of Pediatrics, Division of Neonatology, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Sinno H P
authors.initials: SH
authors.lastname: Simons
authors.affiliation: Department of Medical Microbiology, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Johan W
authors.initials: JW
authors.lastname: Mouton
authors.affiliation: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands Intensive Care and Department of Pediatric Surgery, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands Department of Clinical Pharmacy, St Antonius Hospital, Nieuwegein, The Netherlands c.knibbe@antoniusziekenhuis.nl.
authors.forename: Catherijne A J
authors.initials: CA
authors.lastname: Knibbe
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005839:Gentamicins / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D006801:Humans; D007231:Infant, Newborn; D009010:Monte Carlo Method; D011446:Prospective Studies; D014031:Tobramycin / Q000008:administration & dosage* / Q000493:pharmacokinetics*
chemical_list: D000900:Anti-Bacterial Agents; D005839:Gentamicins; D014031:Tobramycin
keywords: NONMEM; aminoglycosides; pharmacokinetics; therapeutic drug monitoring