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

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posted on 16.12.2020, 09:28 by 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
OBJECTIVE

To investigate the pharmacokinetic and pharmacodynamic properties, and safety of a novel formulation of insulin aspart (AT247) versus currently marketed insulin aspart formulations (IAsp and 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 U/kg) in a random order on three visits. Pharmacokinetics and pharmacodynamics were assessed during a euglycemic clamp lasting up to 8 hours.

RESULTS

Onset of insulin appearance was earlier for AT247 compared with IAsp (−12 minutes [95% CI −14;−8] p=0.0004) and faster IAsp (−2 minutes [−5;−2] p=0.0003). Onset of action was accelerated compared with IAsp (−23 minutes [−37;−15] p=0.0004) and faster IAsp (−9 minutes [−11;−3] p=0.0006). Within the first 60 minutes, a higher exposure was observed for AT247 compared with IAsp (AUCAsp,0-60min: 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 minutes [−58;−15] p=0.0015) and faster IAsp (−27 minutes [−85;−15] p=0.0017), while duration of glucose-lowering effect, measured by tLate50%GIRmax, 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.

Funding

This study was funded by Arecor Limited, UK. D.G., J.J., S.H., L.Z. and F.L. are employees of Arecor Limited. The funding source had no role during the execution of the trial, and in data collection and analyses.

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