title: Altered gentamicin pharmacokinetics in term neonates undergoing controlled hypothermia.
abstract: Little is known about the pharmacokinetic (PK) properties of gentamicin in newborns undergoing controlled hypothermia after suffering from hypoxic−ischaemic encephalopathy due to perinatal asphyxia. This study prospectively evaluates and describes the population PK of gentamicin in these patients
  
  
  
  Demographic, clinical and laboratory data of patients included in a multicentre prospective observational cohort study (the ‘PharmaCool Study’) were collected. A non-linear mixed-effects regression analysis (nonmem®) was performed to describe the population PK of gentamicin. The most optimal dosing regimen was evaluated based on simulations of the final model.
  
  
  
  A total of 47 patients receiving gentamicin were included in the analysis. The PK were best described by an allometric two compartment model with gestational age (GA) as a covariate on clearance (CL). During hypothermia the CL of a typical patient (3 kg, GA 40 weeks, 2 days post-natal age (PNA)) was 0.06 l kg−1 h−1 (inter-individual variability (IIV) 26.6%) and volume of distribution of the central compartment (Vc) was 0.46 l kg−1 (IIV 40.8%). CL was constant during hypothermia and rewarming, but increased by 29% after reaching normothermia (>96 h PNA).
  
  
  
  This study describes the PK of gentamicin in neonates undergoing controlled hypothermia. The 29% higher CL in the normothermic phase compared with the preceding phases suggests a delay in normalization of CL after rewarming has occurred. Based on simulations we recommend an empiric dose of 5 mg kg−1 every 36 h or every 24 h for patients with GA 36–40 weeks and GA 42 weeks, respectively.
authors.affiliation: Department of Pharmacy, Academic Medical Center, Amsterdam.
authors.forename: Yuma A
authors.initials: YA
authors.lastname: Bijleveld
authors.affiliation: Department of Neonatology, Emma Children's Hospital, Academic Medical Center, Amsterdam.
authors.forename: Timo R
authors.initials: TR
authors.lastname: de Haan
authors.affiliation: Pediatric Clinical Research Office, Division Woman-Child, Academic Medical Center, University of Amsterdam, Amsterdam.
authors.forename: Hanneke J H
authors.initials: HJ
authors.lastname: van der Lee
authors.affiliation: Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht.
authors.forename: Floris
authors.initials: F
authors.lastname: Groenendaal
authors.affiliation: Department of Neonatology, University Medical Center Groningen, Groningen.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Dijk
authors.affiliation: Department of Neonatology, Radboud University Medical Center, Nijmegen.
authors.forename: Arno
authors.initials: A
authors.lastname: van Heijst
authors.affiliation: Department of Pediatrics, Division of Neonatology, Erasmus MC-Sophia Children's Hospital, Rotterdam.
authors.forename: Rogier C J
authors.initials: RC
authors.lastname: de Jonge
authors.affiliation: Department of Neonatology, Máxima Medical Center Veldhoven, Veldhoven.
authors.forename: Koen P
authors.initials: KP
authors.lastname: Dijkman
authors.affiliation: Department of Neonatology, Isala Clinics, Zwolle.
authors.forename: Henrica L M
authors.initials: HL
authors.lastname: van Straaten
authors.affiliation: Department of Neonatology, Leiden University Medical Center, Leiden.
authors.forename: Monique
authors.initials: M
authors.lastname: Rijken
authors.affiliation: Department of Neonatology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Inge A
authors.initials: IA
authors.lastname: Zonnenberg
authors.affiliation: Department of Neonatology, Vrije Universiteit Brussel, Brussels.
authors.forename: Filip
authors.initials: F
authors.lastname: Cools
authors.affiliation: Department of Neonatology, Academic Medical Center, Gent, Belgium.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zecic
authors.affiliation: Clinical Research Coordinator PharmaCool Study.
authors.forename: Debbie H G M
authors.initials: DH
authors.lastname: Nuytemans
authors.affiliation: Department of Neonatology, Emma Children's Hospital, Academic Medical Center, Amsterdam.
authors.forename: Anton H
authors.initials: AH
authors.lastname: van Kaam
authors.affiliation: Department of Pharmacy, Academic Medical Center, Amsterdam.
authors.forename: Ron A A
authors.initials: RA
authors.lastname: Mathot
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D015331:Cohort Studies; D003198:Computer Simulation; D005260:Female; D005311:Fetal Hypoxia; D005839:Gentamicins / Q000493:pharmacokinetics*; D005865:Gestational Age; D006801:Humans; D007036:Hypothermia, Induced; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy; D007231:Infant, Newborn; D008297:Male; D015233:Models, Statistical; D011446:Prospective Studies; D017694:Rewarming
chemical_list: D000900:Anti-Bacterial Agents; D005839:Gentamicins
keywords: controlled hypothermia; gentamicin; neonates; population pharmacokinetics