Pharmacokinetics and Pharmacodynamics of a Novel U500 Insulin Aspart Formulation: A Randomized, Double-Blind, Crossover Study in People With Type 1 Diabetes

Abstract

OBJECTIVE To evaluate the pharmacokinetics, pharmacodynamics, and safety of a novel U500 insulin aspart formulation (AT278 U500) compared with insulin aspart (IAsp U100). RESEARCH DESIGN AND METHODS This single-center, randomized, double-blind study was conducted in 38 men with type 1 diabetes (body weight ≤100 kg and total insulin dose <1.2 units/kg/day). Participants received a single dose of either AT278 U500 or IAsp U100 (0.3 units/kg s.c.) in a crossover design, followed by an 8-h euglycemic clamp in the absence of basal insulin. RESULTS With AT278 U500, onset of appearance in serum was 6 min earlier (P < 0.0001) and reached 50% of maximum concentration 23 min faster (P < 0.0001). Insulin exposure with AT278 U500 was 4.0-fold higher within the first 30 min (95% CI 3.29, 4.90), 1.5-fold higher within the first 60 min (95% CI 1.35, 1.76), and statistically superior up to 90 min postdose (P < 0.05). With AT278 U500, onset of action was 10 min earlier (P < 0.0001) and reached 50% of maximum glucose infusion rate 20 min faster (P < 0.0001). The glucose-lowering effect with AT278 U500 was 8.9-fold higher within the first 30 min (95% CI 5.96, 17.46), 2.4-fold higher within the first 60 min (95% CI 1.92, 3.22), and statistically superior up to 2 h postdose (P < 0.0001). Overall insulin exposure and glucose-lowering effect were comparable. No significant safety findings were observed. CONCLUSIONS AT278 U500 offers rapid-acting characteristics in a reduced dose volume, with accelerated absorption and onset of action compared with IAsp U100 in the studied population.

Rethinking the safety and efficacy assessment of (Hybrid) Closed Loop systems: Should we promote the need for a minimum of exercise data within the regulatory approval?

“…However, there may be light at the end of the tunnel as recent data suggest something close to the perfect 'FCL exercise' insulin may be feasible. 10 Notwithstanding, even when we have physiological insulins within a FCL system, we must think about the importance of integrating a minimum amount of physical activity and exercise data into the regulatory safety and efficacy assessments to ensure that these systems work for physically active people with type 1 diabetes (T1D). As physical activity data are often not given separately in analyses, we continue to advise people with HCL systems to follow the recommendations for non-HCL insulin pump therapy 11 : lower the basal rate by up to 80% at least 90 min in advance to exercise, which equates to 'starting the exercise mode' at least 90 min in advance to exercise.…”

“…Furthermore, the delayed on‐set and non‐physiological long duration of rapid‐acting insulins, and the limited CGM performance during rapid glucose changes slow the development of FCL systems. However, there may be light at the end of the tunnel as recent data suggest something close to the perfect ‘FCL exercise’ insulin may be feasible 10 . Notwithstanding, even when we have physiological insulins within a FCL system, we must think about the importance of integrating a minimum amount of physical activity and exercise data into the regulatory safety and efficacy assessments to ensure that these systems work for physically active people with type 1 diabetes (T1D).…”