title: Pharmacokinetics of diluted (U20) insulin aspart compared with standard (U100) in children aged 3-6 years with type 1 diabetes during closed-loop insulin delivery: a randomised clinical trial.
abstract: OBJECTIVE
  The aim of this study was to compare the pharmacokinetics of two different concentrations of insulin aspart (B28Asp human insulin) in children aged 3-6 years with type 1 diabetes.
  
  
  METHODS
  Young children with type 1 diabetes underwent an open-label, randomised, two-period crossover study in a clinical research facility, 2-6 weeks apart. In random order, diluted (1:5 dilution with saline [154 mmol/l NaCl]; 20 U/ml) or standard strength (100 U/ml) insulin aspart was administered via an insulin pump as a meal bolus and then overnight by closed-loop insulin delivery as determined by a model predictive algorithm. Plasma insulin was measured every 30-60 min from 17:00 hours on day 1 to 8:00 hours on day 2. We measured the time-to-peak insulin concentration (tmax), insulin metabolic clearance rate (MCR(I)) and background insulin concentration (ins(c)) using compartmental modelling.
  
  
  RESULTS
  Eleven children (six male; age range 3.75-6.96 years, HbA1c 7.6% ± 1.3% [60 ± 14 mmol/mol], BMI standard deviation score 1.0 ± 0.8, duration of diabetes 2.2 ± 1.0 years, total daily dose 12.9 [10.6-16.5] U, fasting C-peptide concentration 5 [5-17.1] pmol/l; mean ± SD or median [interquartile range]) participated in the study. No differences between standard and diluted insulin were observed in terms of t max (59.2 ± 14.4 vs 61.6 ± 8.7) min for standard vs diluted, p = 0.59; MCR I (1.98 × 10(-2) ± 0.99 × 10(-2) vs 1.89 × 10(-2) ± 0.82 × 10(-2) 1/kg/min, p = 0.47), and ins c (34 [1-72] vs 23 [3-65] pmol/l, p = 0.66). However, t max showed less intersubject variability following administration of diluted aspart (SD 14.4 vs 8.7 min, p = 0.047).
  
  
  CONCLUSIONS
  Diluting insulin aspart does not change its pharmacokinetics. However, it may result in less variable absorption and could be used in young children with type 1 diabetes undergoing closed-loop insulin delivery.
  
  
  BACKGROUND
  Clinicaltrials.gov NCT01557634.
  
  
  BACKGROUND
  FUNDING was provided by the JDRF, 7th Framework Programme of the European Union, Wellcome Trust Strategic Award and the National Institute for Health Research Cambridge Biomedical Research Centre.
authors.affiliation: Department of Paediatrics, University of Cambridge, Cambridge, UK.
authors.forename: Yue
authors.initials: Y
authors.lastname: Ruan
authors.forename: Daniela
authors.initials: D
authors.lastname: Elleri
authors.forename: Janet M
authors.initials: JM
authors.lastname: Allen
authors.forename: Martin
authors.initials: M
authors.lastname: Tauschmann
authors.forename: Malgorzata E
authors.initials: ME
authors.lastname: Wilinska
authors.forename: David B
authors.initials: DB
authors.lastname: Dunger
authors.forename: Roman
authors.initials: R
authors.lastname: Hovorka
mesh_terms: D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D018592:Cross-Over Studies; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D061267:Insulin Aspart / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007332:Insulin Infusion Systems; D008297:Male; D008954:Models, Biological; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D061267:Insulin Aspart