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

Aims/hypothesisThe 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.MethodsYoung 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 (MCRI) and background insulin concentration (insc) using compartmental modelling.ResultsEleven 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 tmax (59.2 ± 14.4 vs 61.6 ± 8.7) min for standard vs diluted, p = 0.59; MCRI (1.98 × 10−2 ± 0.99 × 10−2 vs 1.89 × 10−2 ± 0.82 × 10−2 1/kg/min, p = 0.47), and insc (34 [1–72] vs 23 [3–65] pmol/l, p = 0.66). However, tmax showed less intersubject variability following administration of diluted aspart (SD 14.4 vs 8.7 min, p = 0.047).Conclusions/interpretationDiluting 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 NCT01557634Funding: 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 materialThe 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.

Closing the Loop on Managing Youth With Type 1 Diabetes: Children Are Not Just Small Adults

“…Elleri et al (34) reported that use of diluted insulin during overnight closed-loop control in 3-to 6-year-olds reduced rates of hypoglycemia and tended toward reduced glycemic variability as compared with standard insulin strength. Additionally, analysis of the data from that study demonstrated reduced interindividual variability in time to peak insulin action with diluted insulin (35). The reduced interindividual variability could be attributed to a reduction of mechanical delivery errors and more consistent absorption due to the larger volume of the subcutaneous deposit (35).…”

“…Additionally, analysis of the data from that study demonstrated reduced interindividual variability in time to peak insulin action with diluted insulin (35). The reduced interindividual variability could be attributed to a reduction of mechanical delivery errors and more consistent absorption due to the larger volume of the subcutaneous deposit (35). Hvorka and colleagues are conducting an open-label, randomized crossover assessment of diluted insulin as compared with commercially available insulin preparations in children aged 1-7 years (NCT03101865).…”

ISPAD Clinical Practice Consensus Guidelines 2018: Diabetes technologies

“…Recently, an ISPAD Clinical Practice Consensus Guideline has been released entitled “Managing Diabetes in Preschool Children,” which states pump therapy is the recommended mode of insulin delivery for those under the age of 7 years . In order to overcome the mechanical barrier dictated by the lowest basal and bolus delivery doses feasible with pump therapy, application of diluted insulin to the youngest population has offered the opportunity to more finely tune insulin delivery . While concern is sometimes expressed over how paid care providers will adopt this technology, a study by Weinzimer et al highlighted that children whose parents work outside of home tended to see the largest improvement in glycemic control with transition to pump therapy …”

Challenges in Delivering Smaller Doses of Insulin

“…Of note is that differences in duration of action have been noted at the more concentrated end of the spectrum in U300 glargine 20 and U500R 21 insulin. It is encouraging to note that a recent study by Ruan et al 22 compared U10 or U100 insulin administered by pump with overnight closedloop delivery and showed no difference in pharmacokinetics. However, further study is warranted to understand the pharmacodynamics of diluted insulin in young children and whether varying dilutions behave significantly differently.…”