title: Gentamicin pharmacokinetics and dosing in neonates with hypoxic ischemic encephalopathy receiving hypothermia.
abstract: OBJECTIVE
  To evaluate the pharmacokinetics of gentamicin in neonates with hypoxic ischemic encephalopathy (HIE) receiving hypothermia and to identify an empiric gentamicin dosing strategy in this population that optimizes achievement of target peak and trough concentrations.
  
  
  METHODS
  Population pharmacokinetic study using retrospective medical record data.
  
  
  METHODS
  Tertiary neonatal intensive care unit.
  
  
  METHODS
  A total of 29 full-term neonates diagnosed with HIE treated with hypothermia who received gentamicin and underwent therapeutic drug monitoring
  
  
  RESULTS
  Patient demographics and gentamicin concentration data were retrospectively collected over a 2-year period. A population-based pharmacokinetic model was developed using nonlinear mixed-effects modeling (NONMEM). Using the developed model, Monte Carlo simulations were performed to evaluate the probability of achieving target peak (> 6 mg/L) and trough (< 2 mg/L) gentamicin concentrations for various potential dosing regimens. A one-compartment model best described the available gentamicin concentration data. Birthweight and serum creatinine significantly influenced gentamicin clearance. For the typical study neonate (birthweight 3.3 kg, serum creatinine 0.9 mg/dl), clearance was 0.034 L/hour/kg and volume was 0.52 L/kg. At a 24-hour dosing interval, Monte Carlo simulations predicted target gentamicin peak and trough concentrations could not be reliably achieved at any dose. At a 36-hour dosing interval, a dose of 4-5 mg/kg is predicted to achieve target gentamicin peak and trough concentrations in more than 90% of neonates.
  
  
  CONCLUSIONS
  Gentamicin clearance is decreased in neonates with HIE treated with hypothermia compared with previous reports in nonasphyxiated normothermic full-term neonates. A prolonged 36-hour dosing interval will be needed to achieve target gentamicin trough concentrations in this population. Further prospective evaluation of this dosing recommendation is needed.
authors.affiliation: Department of Pediatrics, Stanford University, Palo Alto, California 94304, USA. frymoyer@stanford.edu
authors.forename: Adam
authors.initials: A
authors.lastname: Frymoyer
authors.forename: Lina
authors.initials: L
authors.lastname: Meng
authors.forename: Sonia L
authors.initials: SL
authors.lastname: Bonifacio
authors.forename: Davide
authors.initials: D
authors.lastname: Verotta
authors.forename: B Joseph
authors.initials: BJ
authors.lastname: Guglielmo
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001724:Birth Weight; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D005839:Gentamicins / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D007036:Hypothermia, Induced / Q000379:methods*; D020925:Hypoxia-Ischemia, Brain / Q000628:therapy*; D007231:Infant, Newborn; D008297:Male; D008954:Models, Biological; D009010:Monte Carlo Method; D017711:Nonlinear Dynamics; D012189:Retrospective Studies; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D005839:Gentamicins; D003404:Creatinine
keywords: gentamicin; hypothermia; hypoxic ischemic encephalopathy; neonates; pharmacokinetics
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