Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of a Single-Dose of NN2211, a Long-Acting Glucagon-Like Peptide 1 Derivative, in Healthy Male Subjects

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.

RETRACTED ARTICLE: A glucagon-like peptide-1 (GLP-1) analogue, liraglutide, upregulates nitric oxide production and exerts anti-inflammatory action in endothelial cells

“…The half-life after intravenous or subcutaneous administration in humans has been reported to be ∼5 min [19]. Liraglutide has been reported to show an elimination half-life of 8.1 h [19].…”

“…The half-life after intravenous or subcutaneous administration in humans has been reported to be ∼5 min [19]. Liraglutide has been reported to show an elimination half-life of 8.1 h [19]. This increase in the halflife of liraglutide is most likely to be mediated via a lower susceptibility to metabolism by DPP-IV [20] and a high degree of albumin binding of liraglutide (as has been shown for other fatty acid derivatives [21,22]); moreover, after subcutaneous administration, an additional prolongation of the half-life is mediated by slow absorption of liraglutide from the injection site, as evidenced by the further increase in half-life observed with subcutaneous vs intravenous administration.…”

“…This increase in the halflife of liraglutide is most likely to be mediated via a lower susceptibility to metabolism by DPP-IV [20] and a high degree of albumin binding of liraglutide (as has been shown for other fatty acid derivatives [21,22]); moreover, after subcutaneous administration, an additional prolongation of the half-life is mediated by slow absorption of liraglutide from the injection site, as evidenced by the further increase in half-life observed with subcutaneous vs intravenous administration. Thus, liraglutide treatment probably induces much higher plasma levels compared with native GLP-1 concentration in plasma [19,23,24]. Therefore, the concentration of liraglutide required to produce beneficial effects in HUVECs (0.1 μg/ml=26.6 nmol/l) might be achievable with the therapeutic doses used to treat patients with type 2 diabetes.…”

Improving function and survival of pancreatic islets by endogenous production of glucagon-like peptide 1 (GLP-1)

“…Unfortunately, the delivery of GLP-1 by injection is hampered by the rapid degradation and clearance of the peptide (14). Moreover, cramping and nausea are common side effects of GLP-1 mimetics and limit the injected doses that are tolerable (15,16). The doses used to promote ␤ cell growth in rodents, typically 50-100 g͞kg of body weight (10,13), are significantly higher than the Ͻ2 g͞kg of body weight dose that is tolerable in humans (17) and greatly exceed the dose of the GLP-1 mimetic exenatide (Byetta) that is currently prescribed to treat type 2 diabetes patients (5 g injected twice daily).…”

One-Step Purification of a Fusion Protein of Glucagon-Like Peptide-1 and Human Serum Albumin Expressed inPichia pastorisby an Immunomagnetic Separation Technique

“…[15][16][17] Liraglutide and CJC-1131 are two GLP-1 analogs with chemical modifications, that can bind noncovalently or covalently to HSA in vivo and exhibited a half-life of more than 10 h above after administration. 18) In addition, Lee et al studied the in vitro and in vivo activity of a PEGylated GLP-1 analog, and the results indicated that it had the bioactivity of native GLP-1, and that its in vivo half-life was significantly prolonged. 12) However, to date, studies of the expression and purification of GLP-1 fusion protein with similar bioactivity have been few.…”