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Clinical Trial
. 2019 May;58(5):639-649.
doi: 10.1007/s40262-018-0718-6.

Clinical Pharmacology of Fast-Acting Insulin Aspart Versus Insulin Aspart Measured as Free or Total Insulin Aspart and the Relation to Anti-Insulin Aspart Antibody Levels in Subjects with Type 1 Diabetes Mellitus

Hanne Haahr  1 , Thomas R Pieber  2 , Chantal Mathieu  3 , Theis Gondolf  4 , Masanari Shiramoto  5 , Lars Erichsen  4 , Tim Heise  6
Affiliations
Clinical Trial

Clinical Pharmacology of Fast-Acting Insulin Aspart Versus Insulin Aspart Measured as Free or Total Insulin Aspart and the Relation to Anti-Insulin Aspart Antibody Levels in Subjects with Type 1 Diabetes Mellitus

Hanne Haahr et al. Clin Pharmacokinet. 2019 May.

Abstract

Background: Fast-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.

Methods: Free 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.

Results: The 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.

Conclusions: Faster 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 identifiers: NCT01618188, NCT02003677, NCT01934712, NCT02568280, NCT01831765.

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Conflict of interest statement

Ethical approval and informed consent

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

Conflict of interest

Hanne Haahr and Lars Erichsen are employees and shareholders of Novo Nordisk. Theis Gondolf is an employee of 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 (a publically funded research centre). Chantal Mathieu serves or has served on advisory panels for Novo Nordisk, Sanofi, Merck Sharp and Dohme, Eli Lilly, Novartis, Bristol-Myers Squibb, AstraZeneca, Pfizer, Janssen Pharmaceuticals, Boehringer Ingelheim, Hanmi Pharmaceuticals, Roche Diagnostics, Medtronic, Mannkind, Intrexon, Dianax and UCB, and as a speaker for Novo Nordisk, Sanofi, Merck Sharp and Dohme, Eli Lilly, Boehringer Ingelheim, AstraZeneca and Novartis. Financial compensation for these activities has been received by KU Leuven. KU Leuven has received research support for Chantal Mathieu from Medtronic, Novo Nordisk, Sanofi, Merck Sharp and Dohme, Eli Lilly, Roche Diagnostics, Abbott, Intrexon and Novartis. Tim Heise is a shareholder of Profil, which has received research funds from Adocia, Boehringer Ingelheim, Dance Pharmaceuticals, Eli Lilly, Johnson & Johnson, MedImmune, Merck Sharp and Dohme, Mylan, Nordic Bioscience, Novo Nordisk, Poxel, Roche Diagnostics, Saniona, Sanofi, Senseonics and Zealand Pharma. In addition, Tim Heise is member of advisory panels for Novo Nordisk and Mylan and received speaker honoraria and travel grants from Dexcom, Eli Lilly, Mylan, Novo Nordisk, Sanofi and Zealand Pharma. Masanari Shiramoto has no conflicts of interest to declare.

Data availability

Will individual participant data be available (including data dictionaries)? Individual participant data will be shared in datasets in a de-identified/anonymised format. What data in particular will be shared? Datasets from Novo Nordisk-sponsored clinical research completed after 2001 for product indications approved in both the EU and USA. What other documents will be available? The study protocol and redacted Clinical Study Report (CSR) will be available according to Novo Nordisk data sharing commitments. When will data be available (start and end dates)? The data will be available permanently after research completion and approval of product and product use in both the EU and USA. There is no end date. With whom will data be shared? With bona fide researchers submitting a research proposal requesting access to data. For what types of analyses? For use as approved by the Independent Review Board (IRB) according to the IRB Charter (see novonordisk-trials.com). By what mechanism will data be made available? Access request proposal form and the access criteria can be found at novonordisk-trials.com. The data will be made available on a specialised SAS® data platform.

Figures

Fig. 1
Fig. 1
Mean serum IAsp concentration–time profiles after subcutaneous faster aspart or IAsp administration in subjects with type 1 diabetes mellitus when using an assay to measure free IAsp (a, c) or total IAsp (b, d). 5-h profiles are shown in a, b, while 2-h profiles are shown in c, d. Mean pharmacokinetic profiles are based on 175 individual profiles per treatment. The dose was adjusted to 0.2 U/kg in all subjects. Variability bands show the standard error of the mean. IAsp insulin aspart
Fig. 2
Fig. 2
Relationship between anti-IAsp antibody level and the ratio of free versus total IAsp exposure in four pooled clinical pharmacology trials (a) and a phase IIIa trial (b) with faster aspart and IAsp. The horizontal dotted line represents similarity between free and total IAsp exposure. Results are based on 175 subjects in the pooled clinical pharmacology trials and 688 (faster aspart) and 352 (IAsp) subjects in the phase IIIa trial. IAsp insulin aspart, %B/T percent bound/total
Fig. 3
Fig. 3
Relationship between anti-IAsp antibody level and total glucose-lowering effect (AUCGIR,0–t) in three pooled clinical pharmacology trials (a) or ΔPPG1 h in a phase IIIa trial (b) with faster aspart and IAsp. Results are based on 112 subjects in the pooled clinical pharmacology trials and 344 (faster aspart) and 348 (IAsp) subjects in the phase IIIa trial. Dotted lines are the estimated regression lines for faster aspart (blue) and IAsp (grey), respectively, including the coefficients of determination (R2) and the p values for a test of the slope being equal to zero (i.e. horizontal regression line). AUCGIR,0–t total area under the curve for glucose infusion rate, IAsp insulin aspart,  %B/T percent bound/total, ΔPPG1 h 1-h postprandial plasma glucose increment
See this image and copyright information in PMC

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