Dataset Information

Elucidating the Mechanism of Absorption of Fast-Acting Insulin Aspart: The Role of Niacinamide.

ABSTRACT:

Purpose

Fast-acting insulin aspart (faster aspart) is a novel formulation of insulin aspart containing two additional excipients: niacinamide, to increase early absorption, and L-arginine, to optimize stability. The aim of this study was to evaluate the impact of niacinamide on insulin aspart absorption and to investigate the mechanism of action underlying the accelerated absorption.

Methods

The impact of niacinamide was assessed in pharmacokinetic analyses in pigs and humans, small angle X-ray scattering experiments, trans-endothelial transport assays, vascular tension measurements, and subcutaneous blood flow imaging.

Results

Niacinamide increased the rate of early insulin aspart absorption in pigs, and pharmacokinetic modelling revealed this effect to be most pronounced up to ~30-40 min after injection in humans. Niacinamide increased the relative monomer fraction of insulin aspart by ~35%, and the apparent permeability of insulin aspart across an endothelial cell barrier by ~27%. Niacinamide also induced a concentration-dependent vasorelaxation of porcine arteries, and increased skin perfusion in pigs.

Conclusion

Niacinamide mediates the acceleration of initial insulin aspart absorption, and the mechanism of action appears to be multifaceted. Niacinamide increases the initial abundance of insulin aspart monomers and transport of insulin aspart after subcutaneous administration, and also mediates a transient, local vasodilatory effect.

SUBMITTER: Kildegaard J

PROVIDER: S-EPMC6373292 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Publications

Elucidating the Mechanism of Absorption of Fast-Acting Insulin Aspart: The Role of Niacinamide.

Kildegaard Jonas J Buckley Stephen T ST Nielsen Rasmus H RH Povlsen Gro K GK Seested Torben T Ribel Ulla U Olsen Helle B HB Ludvigsen Svend S Jeppesen Claus B CB Refsgaard Hanne H F HHF Bendtsen Kristian M KM Kristensen Niels R NR Hostrup Susanne S Sturis Jeppe J

Pharmaceutical research 20190211 3

<h4>Purpose</h4>Fast-acting insulin aspart (faster aspart) is a novel formulation of insulin aspart containing two additional excipients: niacinamide, to increase early absorption, and L-arginine, to optimize stability. The aim of this study was to evaluate the impact of niacinamide on insulin aspart absorption and to investigate the mechanism of action underlying the accelerated absorption.<h4>Methods</h4>The impact of niacinamide was assessed in pharmacokinetic analyses in pigs and humans, sma ...[more]

PMID: 30746556

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Project description:BackgroundFast-acting insulin aspart (faster aspart) is an ultra-fast-acting formulation of insulin aspart (IAsp). This post hoc analysis investigated the pharmacokinetics of faster aspart versus IAsp, measured as free or total IAsp, and the relationship between anti-IAsp antibodies and the pharmacokinetics/pharmacodynamics of faster aspart and IAsp.MethodsFree and total IAsp concentrations and anti-IAsp antibodies were determined in adults with type 1 diabetes mellitus receiving subcutaneous faster aspart and/or IAsp in four single-dose clinical pharmacology trials (n = 175) and a 26-week phase IIIa trial (n = 1040). Pharmacodynamics were assessed by euglycaemic clamp or meal test, respectively.ResultsThe pharmacokinetic profile was left-shifted and early exposure was greater with faster aspart versus IAsp independent of free or total IAsp assay. The faster aspart-IAsp difference in the time to 50% of maximum IAsp concentration in the early part of the pharmacokinetic profile (tEarly 50 % Cmax) [95% confidence interval (CI)] was - 8.8 [- 10.0 to - 7.5] and - 7.6 [- 8.8 to - 6.4] min for free and total IAsp, respectively. The faster aspart/IAsp ratio for the area under the concentration-time curve (AUC) for IAsp from time zero to 30 min (AUCIAsp,0-30 min) [95% CI] was 1.88 [1.74-2.04] and 1.77 [1.64-1.90] for free and total IAsp. Higher anti-IAsp antibody levels were associated with a lower ratio of free/total IAsp for the total AUC for IAsp (AUCIAsp,0-t). Early glucose-lowering effect (AUC for the glucose infusion rate [GIR] from time zero to 60 min [AUCGIR,0-60 min]) was greater by 25-44% for faster aspart versus IAsp independent of anti-IAsp antibody levels. Total glucose-lowering effect (total AUC for GIR [AUCGIR,0-t]) in a clamp and 1-h postprandial glucose increment in a meal test appeared essentially unaffected by anti-IAsp antibodies.ConclusionsFaster aspart provides accelerated pharmacokinetics versus IAsp regardless if based on free or total IAsp assay. Higher anti-IAsp antibodies increase total IAsp concentrations but do not influence faster aspart nor IAsp pharmacodynamics. CLINICALTRIALS.Gov identifiersNCT01618188, NCT02003677, NCT01934712, NCT02568280, NCT01831765.

Project description:AimsTo investigate the pharmacokinetic/pharmacodynamic properties of fast-acting insulin aspart (faster aspart) versus insulin aspart (IAsp) in people with type 2 diabetes (T2D).Materials and methodsIn a randomized, double-blind, crossover design, 61 people with T2D usually treated with insulin ± oral antidiabetic drug(s) received single-dose faster aspart and IAsp (0.3 U/kg) on separate visits. Blood samples for pharmacokinetic assessment were collected frequently until 12 hours post-dose. Glucose-lowering effect was determined in a euglycaemic clamp lasting up to 12 hours post-dose (target 5.0 mmol/L).ResultsThe serum IAsp pharmacokinetic profile and glucose-lowering effect profile were shifted to the left for faster aspart versus IAsp. Least squares mean (± SE) onset of appearance was 3.3 ± 0.3 minutes for faster aspart, which was 1.2 minutes earlier than for IAsp (95% confidence interval [CI] -1.8;-0.5; P = .001). Onset of action for faster aspart was 8.9 minutes earlier (95% CI -12.1;-5.7; P < .001) than for IAsp. During the first 30 minutes after dosing, 89% larger IAsp exposure (ratio faster aspart/IAsp 1.89 [95% CI 1.56;2.28]; P < .001) and 147% greater glucose-lowering effect (2.47 [95% CI 1.58;6.22]; P < .001) were observed for faster aspart compared with IAsp. Offset of exposure (time to 50% of maximum IAsp concentration in the late part of the pharmacokinetic profile) occurred earlier for faster aspart (difference faster aspart - IAsp -36.4 minutes [95% CI -55.3;-17.6]; P < .001). The treatment difference of faster aspart - IAsp in offset of glucose-lowering effect (time to 50% of maximum glucose infusion rate in the late part of the glucose infusion rate profile) was -14.4 minutes (95% CI -34.4;5.5; P = .152).ConclusionsIn people with T2D, faster aspart was associated with earlier onset and greater initial exposure and glucose-lowering effect compared with IAsp, as previously shown in people with type 1 diabetes.

Dataset Information

Elucidating the Mechanism of Absorption of Fast-Acting Insulin Aspart: The Role of Niacinamide.

Purpose

Methods

Results

Conclusion

Publications

Elucidating the Mechanism of Absorption of Fast-Acting Insulin Aspart: The Role of Niacinamide.

Similar Datasets

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