Pharmacokinetics, pharmacodynamics, safety, and tolerability of a single-dose of NN2211, a long-acting glucagon-like peptide 1 derivative, in healthy male subjects
Date
2002
Authors
Elbrond, B.
Jakobsen, G.
Larsen, S.
Agerso, H.
Jensen, L.
Rolan, P.
Sturis, J.
Hatorp, V.
Zdravkovic, M.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Diabetes Care, 2002; 25(8):1398-1404
Statement of Responsibility
Bodil Elbrønd, Grethe Jakobsen, Søren Larsen, Henrik Agersø, Lisbeth Bjerring Jensen, Paul Rolan, Jeppe Sturis, Vibeke Hatorp, and Milan Zdravkovic
Conference Name
Abstract
OBJECTIVE—The primary objective of the present study was to investigate the safety, tolerability, and pharmacokinetics of a single dose of NN2211, a long-acting glucagon-like peptide 1 (GLP-1) derivative, in healthy male subjects. The secondary objective was to investigate the pharmacodynamics of NN2211. RESEARCH DESIGN AND METHODS—In a double-blind, randomized dose, escalation, placebo-controlled study, healthy male subjects were enrolled at eight consecutive dose levels (1.25, 2.5, 5.0, 10.0, 12.5, 15.0, 17.5, and 20.0 µg/kg) with eight subjects per dose level at a 3:1 active:placebo randomization. After subcutaneous dosing with NN2211, 48-h pharmacokinetic, and 24-h glucose, insulin and glucagon profiles were assessed. In addition, three subjects at each dose level were randomly assigned (one placebo/two active) to an intravenous glucose tolerance test (IVGTT) 9 h after the dose (corresponding to the time to maximal plasma concentration of NN2211). RESULTS—After subcutaneous administration, the half-life of NN2211 was found to be 11–15 h. Overall, although there were no statistically significant differences compared with placebo in the area under the curve (0–9 h for insulin or glucagon), there was a borderline- significant lowering of glucose levels (P = 0.066). During the IVGTT, there was a statistically significant increase in insulin secretion (P = 0.0002), but there was no significant effect on glucagon levels. Although no significant effect was observed on glucose levels during the IVGTT, there was a dose-dependent increase in the glucose disappearance constant. Whereas no serious adverse events were observed, there was a higher incidence of adverse events after active treatment compared with placebo treatment (notably headache, dizziness, nausea, and vomiting). CONCLUSIONS—This study provides evidence that NN2211 has a pharmacokinetic profile consistent with once-daily dosing in humans