Pharmacokinetics and Pharmacodynamics of Three Different Formulations of Insulin Aspart: A Randomized, Double-Blind, Crossover Study in Men With Type 1 Diabetes

Eva Svehlikova, Ines Mursic, Thomas Augustin, Christoph Magnes, David Gerring, Jan Jezek, Daniela Schwarzenbacher, Maria Ratzer, Michael Wolf, Sarah Howell, Leon Zakrzewski, Martina Urschitz, Bernd Tschapeller, Christina Gatschelhofer, Franz Feichtner, Fiona Lawrence, Thomas R Pieber, Eva Svehlikova, Ines Mursic, Thomas Augustin, Christoph Magnes, David Gerring, Jan Jezek, Daniela Schwarzenbacher, Maria Ratzer, Michael Wolf, Sarah Howell, Leon Zakrzewski, Martina Urschitz, Bernd Tschapeller, Christina Gatschelhofer, Franz Feichtner, Fiona Lawrence, Thomas R Pieber

Abstract

Objective: To investigate the pharmacokinetic and pharmacodynamic properties and safety of a novel formulation of insulin aspart (AT247) versus two currently marketed insulin aspart formulations (NovoRapid [IAsp] and Fiasp [faster IAsp]).

Research design and methods: This single-center, randomized, double-blind, three-period, crossover study was conducted in 19 men with type 1 diabetes, receiving single dosing of trial products (0.3 units/kg) in a random order on three visits. Pharmacokinetics and pharmacodynamics were assessed during a euglycemic clamp lasting up to 8 h.

Results: Onset of insulin appearance was earlier for AT247 compared with IAsp (-12 min [95% CI -14; -8], P = 0.0004) and faster IAsp (-2 min [-5; -2], P = 0.0003). Onset of action was accelerated compared with IAsp (-23 min [-37; -15], P = 0.0004) and faster IAsp (-9 min [-11; -3], P = 0.0006). Within the first 60 min, a higher exposure was observed for AT247 compared with IAsp by the area under the curve (AUC) glucose infusion rate (GIR) from 0 to 60 min (AUCAsp0-60min: treatment ratio vs. IAsp 2.3 [1.9; 2.9] vs. faster IAsp 1.5 [1.3; 1.8]), which was underpinned by a greater early glucose-lowering effect (AUCGIR,0-60min: treatment ratio vs. IAsp 2.8 [2.0; 5.5] vs. faster IAsp 1.7 [1.3; 2.3]). Furthermore, an earlier offset of exposure was observed for AT247 compared with IAsp (-32 min [-58; -15], P = 0.0015) and faster IAsp (-27 min [-85; -15], P = 0.0017), while duration of the glucose-lowering effect, measured by time to late half-maximum effect, did not differ significantly.

Conclusions: AT247 exhibited an earlier insulin appearance, exposure, and offset, with corresponding enhanced early glucose-lowering effect compared with IAsp and faster IAsp. It therefore represents a promising candidate in the pursuit for second-generation prandial insulin analogs to improve postprandial glycemic control.

Trial registration: ClinicalTrials.gov NCT03959514.

© 2020 by the American Diabetes Association.

Figures

Figure 1
Figure 1
Pharmacokinetic and pharmacodynamic profiles after subcutaneous administration of 0.3 units/kg of a novel insulin aspart formulation (AT247), IAsp, or faster IAsp in men with type 1 diabetes. Serum insulin aspart concentration-time profiles for 8 h (A) and 2 h (B) postdose, and GIR-time profiles for 8 h (C) and 2 h (D) postdose. The GIR was averaged over 5-min intervals for the first 2 h, while 10-min intervals were used for the remaining time. Variability bands show the SEM. Number of participants: 19 for AT247 and faster IAsp; and 18 for IAsp.
Figure 2
Figure 2
Exposure (A) and glucose-lowering effect (B) for a novel formulation of insulin aspart (AT247) vs. IAsp and faster IAsp. Number of participants: 19 for AT247 and faster IAsp; 18 for IAsp. Treatment ratios (95% CI) were calculated using the Fieller method (28). *Treatment ratios (AT247-to-IAsp and AT247-to-faster IAsp) were not calculable. †CI was not calculable.

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