title: Urinary kidney injury biomarkers and tobramycin clearance among children and young adults with cystic fibrosis: a population pharmacokinetic analysis.
abstract: Tobramycin is frequently used for treatment of bronchopneumonia in patients with cystic fibrosis (CF). Variability in tobramycin clearance (CL) is high in this population with few reliable approaches to guide dosing.
  
  
  
  We sought to evaluate the pharmacokinetics of once-daily intravenous tobramycin in patients with CF and test the influence of covariates on tobramycin CL, including serum creatinine (SCr) and urinary biomarkers: neutrophil gelatinase-associated lipocalin (NGAL), retinol-binding protein (RBP) and kidney injury molecule-1 (KIM-1).
  
  
  
  This was a prospective, observational cohort study of children/young adults with CF receiving once-daily intravenous tobramycin from October 2012 to May 2014 at Cincinnati Children's Hospital Medical Center. Therapeutic drug monitoring data were prospectively obtained. Population pharmacokinetic analyses were performed using non-linear mixed-effects modelling.
  
  
  
  Thirty-seven patients (median age 15.3 years, IQR 12.7-19.5) received 62 tobramycin courses. A one-compartment model with allometrically scaled weight for tobramycin CL and volume of distribution (V) best described the data. Urinary NGAL was associated with tobramycin CL (P < 0.001), as was urinary RBP (P < 0.001). SCr, estimated glomerular filtration rate and urinary KIM-1 were not significant covariates. The population pharmacokinetic parameter estimates were CL = 8.60 L/h/70 kg (relative standard error 4.3%) and V = 31.3 L/70 kg (relative standard error 4.7%).
  
  
  
  We describe urinary biomarkers as predictors of tobramycin CL using a population pharmacokinetic modelling approach. Our findings suggest that patient weight and urinary NGAL or RBP could be used to individualize tobramycin therapy in patients with CF.
authors: Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA downeskj@email.chop.edu.|Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors: Kevin J
authors: KJ
authors: Downes
authors: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors: Min
authors: M
authors: Dong
authors: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.|Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors: Tsuyoshi
authors: T
authors: Fukuda
authors: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.|Division of Pulmonology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors: John P
authors: JP
authors: Clancy
authors: Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors: Christopher
authors: C
authors: Haffner
authors: Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors: Michael R
authors: MR
authors: Bennett
authors: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.|Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors: Alexander A
authors: AA
authors: Vinks
authors: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.|Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors: Stuart L
authors: SL
authors: Goldstein
mesh_terms: D061605:Administration, Intravenous; D000293:Adolescent; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015415:Biomarkers / Q000032:analysis*; D001996:Bronchopneumonia / Q000150:complications / Q000188:drug therapy*; D002648:Child; D003404:Creatinine / Q000097:blood; D003550:Cystic Fibrosis / Q000150:complications*; D016903:Drug Monitoring; D005260:Female; D000072596:Hepatitis A Virus Cellular Receptor 1 / Q000032:analysis; D006776:Hospitals, Pediatric; D006801:Humans; D000071068:Lipocalin-2 / Q000652:urine; D008297:Male; D008657:Metabolic Clearance Rate; D009820:Ohio; D010865:Pilot Projects; D011446:Prospective Studies; D051436:Renal Insufficiency, Chronic / Q000175:diagnosis / Q000473:pathology*; D012177:Retinol-Binding Proteins / Q000652:urine; D014031:Tobramycin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D015415:Biomarkers; C491143:HAVCR1 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D012177:Retinol-Binding Proteins; D003404:Creatinine; D014031:Tobramycin