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. 2017 May;56(5):551-559.
doi: 10.1007/s40262-017-0514-8.

A Pooled Analysis of Clinical Pharmacology Trials Investigating the Pharmacokinetic and Pharmacodynamic Characteristics of Fast-Acting Insulin Aspart in Adults with Type 1 Diabetes

Tim Heise  1 , Thomas R Pieber  2 , Thomas Danne  3 , Lars Erichsen  4 , Hanne Haahr  4
Affiliations

A Pooled Analysis of Clinical Pharmacology Trials Investigating the Pharmacokinetic and Pharmacodynamic Characteristics of Fast-Acting Insulin Aspart in Adults with Type 1 Diabetes

Tim Heise et al. Clin Pharmacokinet. 2017 May.

Abstract

Background: Fast-acting insulin aspart (faster aspart) is insulin aspart (IAsp) in a new formulation aiming to mimic the fast endogenous prandial insulin release more closely than currently available insulin products. In a post hoc analysis of pooled data from six clinical pharmacology trials, the pharmacological characteristics of faster aspart and IAsp were compared.

Methods: The analysis included 218 adult subjects with type 1 diabetes from six randomised, double-blind, crossover trials in the faster aspart clinical development programme. Subjects received subcutaneous dosing (0.2 U/kg) of faster aspart and IAsp. In three trials, a 12-h euglycaemic clamp was performed (target 5.5 mmol/L; 100 mg/dL) to assess pharmacodynamics.

Results: The pharmacokinetic and pharmacodynamic profiles were left-shifted for faster aspart versus IAsp. Onset of appearance occurred 4.9 min earlier (95% confidence interval [CI] faster aspart-IAsp: [-5.3 to -4.4], p < 0.001), early exposure (AUCIAsp,0-30min) was two times greater (estimated ratio faster aspart/IAsp 2.01 [1.87-2.17], p < 0.001) and offset of exposure (t Late 50% Cmax) occurred 12.2 min earlier [-17.9 to -6.5] (p < 0.001) for faster aspart versus IAsp. Accordingly, onset of action occurred 4.9 min earlier [-6.9 to -3.0] (p < 0.001), early glucose-lowering effect (AUCGIR,0-30min) was 74% greater (1.74 [1.47-2.10], p < 0.001) and offset of glucose-lowering effect (t Late 50% GIRmax) occurred 14.3 min earlier [-22.1 to -6.5] (p < 0.001) for faster aspart versus IAsp. Total exposure and total glucose-lowering effect did not differ significantly between treatments.

Conclusions: Faster aspart has the potential to better mimic the physiologic prandial insulin secretion and thereby to improve postprandial glucose control compared with IAsp. ClinicalTrials.gov identifiers: NCT02035371, NCT01924637, NCT02131246, NCT02033239, NCT02003677, NCT01618188.

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Conflict of interest statement

Funding

This investigation was funded by Novo Nordisk.

Conflicts of interest

Tim Heise is shareholder of Profil, which has received research funds from Adocia, AstraZeneca, Becton–Dickinson, Biocon, Boehringer Ingelheim, Dance Biopharm, Eli Lilly, Grünenthal, Gulf Pharmaceutical Industries, Johnson & Johnson, Marvel, MedImmune, Medtronic, Novartis, Novo Nordisk, Roche Diagnostics, Sanofi, Senseonics and Zealand Pharma. In addition, Tim Heise is member of advisory panels for Novo Nordisk and received speaker honoraria and travel grants from Eli Lilly, Mylan and Novo Nordisk. Thomas R. Pieber has received research support from AstraZeneca and Novo Nordisk, has served in advisory panels for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Novo Nordisk and Roche Diabetes Care, and is an employee of CBmed—Center for Biomarker Research in Medicine. Thomas Danne has received research support from and/or has served in advisory panels for Abbott, Bayer, Boehringer Ingelheim, Dexcom, Eli Lilly, Medtronic, Novo Nordisk, Roche, Sanofi and Ypsomed, and is a shareholder of DreaMed Diabetes. Lars Erichsen and Hanne Haahr are employees and shareholders of Novo Nordisk.

Figures

Fig. 1
Fig. 1
Pharmacokinetic and pharmacodynamic profiles following a subcutaneous dose of 0.2 U/kg faster aspart or IAsp in a pooled analysis of subjects with type 1 diabetes: mean serum IAsp concentration–time profiles for a 5 h and c 2 h after injection, and mean glucose-lowering effect profiles for b 5 h and d 2 h after injection. Mean pharmacokinetic profiles are based on 261 individual profiles for faster aspart and 256 individual profiles for IAsp, while mean pharmacodynamic profiles are based on 163 individual profiles for faster aspart and 160 individual profiles for IAsp. Variability bands show the standard error of the mean. IAsp insulin aspart
Fig. 2
Fig. 2
Early exposure for faster aspart versus IAsp following a subcutaneous dose of 0.2 U/kg in subjects with type 1 diabetes in each of the trials and pooled. For the pooled analysis, exposure endpoints are based on 261 profiles for faster aspart and 256 profiles for IAsp. AUC area under the curve, CI confidence interval, IAsp insulin aspart
Fig. 3
Fig. 3
Early glucose-lowering effect for faster aspart versus IAsp following a subcutaneous dose of 0.2 U/kg in subjects with type 1 diabetes in each of the trials and pooled. For the pooled analysis, glucose-lowering effect endpoints are based on 163 profiles for faster aspart and 160 profiles for IAsp. AUC area under the curve, CI confidence interval, GIR glucose infusion rate, IAsp insulin aspart
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