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Clin Pharmacokinet. 2018 Nov 7. doi: 10.1007/s40262-018-0718-6. [Epub ahead of print]

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.

Author information

1
Novo Nordisk A/S, Vandtårnsvej 114, 2860, Søborg, Denmark. hhaa@novonordisk.com.
2
Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria.
3
Clinical and Experimental Endocrinology, University Hospital Leuven, KU Leuven, UZ Herestraat 49, Box 902, 3000, Leuven, Belgium.
4
Novo Nordisk A/S, Vandtårnsvej 114, 2860, Søborg, Denmark.
5
SOUSEIKAI, Hakata Clinic, 6-18 Tenyamachi, Hakata-ku, Fukuoka, 812-0025, Japan.
6
Profil, Hellersbergstrasse 9, 41460, Neuss, Germany.

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.

PMID:
30402720
DOI:
10.1007/s40262-018-0718-6

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