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

AIMS/HYPOTHESIS: 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 (t (max)), 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, HbA(1c) 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/INTERPRETATION: 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. Trial registration: Clinicaltrials.gov NCT01557634 Funding: 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-014-3483-6) contains peer-reviewed but unedited supplementary material, which is available to authorised users.