title: Predictive performance of a gentamicin population pharmacokinetic model in neonates receiving full-body hypothermia.
abstract: BACKGROUND
  Population pharmacokinetic (popPK) models derived from small pharmacokinetics (PK) studies in neonates are often underpowered to detect clinically important characteristics that drive dosing. External validation of such models is crucial. In this study, the predictive performance of a gentamicin popPK model in neonates receiving hypothermia was evaluated.
  
  
  METHODS
  A previously published gentamicin popPK model was developed in neonates with hypoxic ischemic encephalopathy undergoing hypothermia using a retrospective single-institution (University of California-San Francisco) data set. The predictive performance of this model was evaluated in an external retrospective data set from the University of California-San Francisco (validation A) and another from Duke University (validation B). Both institutions used the same hypothermia protocol and collected similar clinical and PK data. Gentamicin dosing and samples were collected per routine care. Predictive performance was evaluated by quantifying the accuracy and precision of model predictions and using simulation-based diagnostics to detect bias in predictions.
  
  
  RESULTS
  Forty-one neonates (n = 18 validation A; n = 23 validation B) with median (range) gestational age of 40 weeks (33-42) and birth weight of 3.3 kg (1.9-4.6) and 76 samples (55% troughs, 33% and 28% drawn at 24 and 36 hours after dose, respectively) were analyzed. The model adequately predicted gentamicin concentrations from the same institution (validation A; median average fold error = 1.1 and numerical prediction distribution error P > 0.05) but underpredicted concentrations from the outside institution (validation B; median average fold error = 0.6 and numerical prediction distribution error P < 0.05).
  
  
  CONCLUSIONS
  The model demonstrated adequate predictive performance for an external data set in the same institution but not from an outside institution. Larger sample sizes, use of data from multiple institutions, and external evaluation in development of popPK models in neonates may improve generalizability of dosing recommendations arising from single-institution studies.
authors.affiliation: *Duke Clinical Research Institute, Durham; †Department of Pharmacotherapy and Experiment Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC; ‡Department of Pediatrics, Stanford University, Palo Alto, CA; §Department of Pediatrics, Duke University Medical Center, Durham, NC; ¶Schools of Medicine and Pharmacy, University of California San Diego, La Jolla; and ‖Department of Pediatrics, University of California, San Francisco.
authors.forename: Mario R
authors.initials: MR
authors.lastname: Sampson
authors.forename: Adam
authors.initials: A
authors.lastname: Frymoyer
authors.forename: Benjamin
authors.initials: B
authors.lastname: Rattray
authors.forename: C Michael
authors.initials: CM
authors.lastname: Cotten
authors.forename: P Brian
authors.initials: PB
authors.lastname: Smith
authors.forename: Edmund
authors.initials: E
authors.lastname: Capparelli
authors.forename: Sonia L
authors.initials: SL
authors.lastname: Bonifacio
authors.forename: Michael
authors.initials: M
authors.lastname: Cohen-Wolkowiez
mesh_terms: D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D005839:Gentamicins / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007036:Hypothermia, Induced; D007231:Infant, Newborn; D008297:Male; D008954:Models, Biological; D015203:Reproducibility of Results; D012189:Retrospective Studies
chemical_list: D000900:Anti-Bacterial Agents; D005839:Gentamicins